BR112020005537A2 - composition, combination of inositol and alpha-lactalbumin for use, use of inositol, kit and food or drink product - Google Patents

Abstract

The present invention relates, among other things, to compositions that are used for the treatment of infertility or subfertility, in particular infertility or subfertility caused by polycystic ovary syndrome (PCOS) or anovulation or that are suitable for the treatment of PCOS or anovulation itself.

Description

Invention Patent Descriptive Report COMPOSITION, COMBINATION OF INOSITOL AND ALPHA-LACTALBUMIN FOR USE, USE OF INOSITOL, KIT AND FOOD OR DRINK PRODUCT Field of the Invention

[0001] The present invention relates to compositions that are suitable for the treatment of infertility or subfertility, in particular infertility or subfertility caused by polycystic ovary syndrome (PCOS) or anovulation, or that are suitable for the treatment of PCOS or anovulation itself said. The compositions comprise inositol and alpha-lactalbumin in defined weight ratios. The invention also relates to a combination of inositol and alpha-lactalbumin, characterized by being for use as a medicine. The invention further relates to inositol in combination with alpha-lactalbumin for use in a method of treating infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, or for use in a method of treating PCOS or anovulation itself . The invention further relates to a method of treating infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, or PCOS treatment or anovulation itself. The invention also relates to a kit of parts comprising inositol and alpha-lactalbumin. The invention also relates to a food product or beverage comprising inositol and alpha-lactalbumin.

Background of the Invention

[0002] Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders, with a variety of metabolic and endocrine abnormalities and clinical symptoms. It is a chronic condition with implications for morbidities, both in the short term, such as subfertility and pregnancy-related complications, as well as long-term risks, such as diabetes,

cardiovascular diseases, poor quality of life and general mortality. The diagnostic characteristics of polycystic ovary syndrome are hyperandrogenism, chronic oligo-ovulation or anovulation and polycystic ovaries. Medical treatment of PCOS aims to restore fertility, treat hirsutism (abnormal hair growth on a woman's face and body) or acne and restore ovulation.

[0003] It is known that inositol, in particular myo-inositol, is effective in restoring spontaneous ovarian activity and, consequently, in fertility in most patients with PCOS. For example, oral treatment with 2 g of myo-inositol twice daily has been clinically investigated in several trials and can be considered one of the standard PCOS treatments.

[0004] Despite this, neither inositol, in particular myo-inositol, nor other pharmacological treatments (eg, metformin, clomiphene citrate, etc.) are always completely effective in the treatment of PCOS or associated conditions, such as anovulation, fertility and subfertility in all patients. This may be related to the variation in individual responses to the same treatment. In fact, Kamenov et al. (Gynecol. Endocrinol. February 2015; 31 (2): 131-5), reported that the treatment of women with anovulatory PCOS with myo-inositol 4 g / day still resulted in 38.3% of the non-responders, that is, patients who, after said treatment, did not ovulate. Thus, although the important role of myo-inositol in human reproduction is known, and although myo-inositol supplementation has been proposed as a reliable treatment in women affected by PCOS, there is still significant room for improvement in the treatment of infertility or subfertility , in particular infertility or subfertility caused by PCOS or anovulation, with inositols, in particular with myo-inositol.

[0005] Lactalbumin belongs to the broadest class of "whey proteins" and is the albumin contained in milk and obtained from whey. It is present in the milk of many mammals, including breast milk. Lactalbumin exists in two distinct but structurally related forms, alpha-lactalbumin and beta-lactalbumin. Studies suggest that alpha-lactalbumin exerts a gastroprotective activity in experimental models of gastric ulcer induced by ethanol or stress (Matsumoto H, Shimokawa Y, Ushida Y, Toida T, Hayasawa H. New biological function of bovine alpha lactalbumin: protective effect against ethanol- and stress-induced gastric mucosal injury in rats. Biosci. Biotechnol. Biochem. May 2001; 65 (5): 1104-11). Alpha-lactalbumin strengthens the mucus gel layer in the gastric mucosa in vivo, increasing the mucin content of the mucus gel layer in the rat gastric mucosa (Ushida Y, Shimokawa Y, Toida T, Matsui H, Takase M. Bovine alpha lactalbumin stimulates mucus metabolism in gastric mucosa. J. Dairy Sci. February 2007; 90 (2): 541-6). By stimulating glucagon-like peptide 2 (GLP-2), alpha-lactalbumin contributes to the growth and maturation of the small intestine. For example, it stimulates proliferation and suppresses apoptosis in intestinal epithelial cells, resulting in an increase in the height of the cryptovilli and mass of the small intestine. Alpha-lactalbumin can serve as an illustrative example of a "hybrid moonlighting protein", whose various functions depend on its location and environment, and range from participation in lactose biosynthesis in the lactating mammary gland to contribution to antiviral, antimicrobial activity and anti-tumor of milk and also includes involvement in several transport functions. In addition, the structure, conformational properties and functions of alpha-lactalbumin are regulated by the bonding of metal ions. EP 1 228 707 A1 describes alpha-lactalbumin as a prebiotic agent, as well as its use for the treatment of gastroenteritis and salmonella infections.

[0006] It is an objective of the present invention to provide improved compositions, uses and methods to alleviate medical conditions such as infertility and subfertility, in particular infertility and subfertility caused by PCOS or anovulation. It is also an objective of the present invention to provide improved compositions, uses and methods to alleviate such conditions as PCOS and anovulation itself.

Summary of the Invention

[0007] One aspect of the invention provides a composition, characterized in that it comprises inositol and alpha-lactalbumin, in which inositol and alpha-lactalbumin are present in a respective weight ratio of about 1: 1 to 50: 1.

[0008] A further aspect of the invention provides a combination of inositol and alpha-lactalbumin for use as a medicament.

[0009] A further aspect of the invention provides inositol for use in a method of treating or preventing infertility or subfertility, in particular infertility or subfertility caused by polycystic ovary syndrome (PCOS) or anovulation, in an individual, wherein the method comprises administer inositol to the individual in combination with alpha-lactalbumin. In a related aspect, the invention provides inositol, for use in a method of treating or preventing polycystic ovary syndrome (PCOS) or anovulation in an individual, wherein the method comprises administering inositol to the individual in combination with alpha-lactalbumin.

[0010] A further aspect of the invention provides a method of treating or preventing infertility or subfertility, in particular infertility or subfertility caused by polycystic ovary syndrome (PCOS) or anovulation in an individual who needs or potentially needs it, where the method it comprises administering a therapeutically or prophylactically effective amount of inositol to the individual in combination with alpha-lactalbumin. In a related aspect, the invention provides a method of treating or preventing polycystic ovary syndrome (PCOS) or anovulation in an individual who needs or potentially needs it, wherein the method comprises administering a therapeutic or prophylactically effective amount of inositol to the individual in combination with alpha-lactalbumin.

[0011] A further aspect of the invention provides a kit of parts comprising inositol in a first container and alpha-lactalbumin in a second container.

[0012] A further aspect of the invention provides a food or drink product, characterized in that it comprises inositol and alpha-lactalbumin in which the respective weight ratio between inositol and alpha-lactalbumin is about 1: 1 to 50: 1.

Brief Description of the Figures

[0013] Figure 1 is a graph of data obtained in a 2-phase study, which demonstrates that the plasma concentration of myo-inositol was significantly higher in patients who received myo-inositol with alpha-lactalbumin than in patients who received myo-inositol without alpha-lactalbumin. The bottom graph shows the plasma level of myo-inositol versus the time when myo-inositol is administered alone. The upper graph shows the plasma level of myo-inositol versus the time when myo-inositol is administered in combination with alpha-lactalbumin. The shaded portion between the upper and lower graphs illustrates the increased area under the curve for the plasma concentration of myo-inositol versus the time obtained by the combined administration of myo-inositol and alpha-lactalbumin, compared to the administration with only myo-inositol .

Detailed Description of the Invention

[0014] In the following, definitions are provided of various terms and expressions used in the present application to describe the invention. Some terms (for example, inositol, alpha-lactalbumin, composition, etc.) are listed identically in the description of different aspects or embodiments of the invention. It is to be understood that definitions of terms and expressions used in more than one aspect of the invention apply equally to any aspect of the invention described herein, in which those terms and expressions appear. This applies equally, regardless of where, that is, which section, in the present application, such terms are defined or discussed.

[0015] In this application, the use of the singular (for example, "one, one" or "o, a") may include the plural unless specifically indicated otherwise. In addition, the use of the term "including", as well as other grammatical forms, such as "includes" and "included", is not limiting.

[0016] As used herein, the term "comprising" has the broad standard meaning "including", "encompassing" or "containing". It includes the element (s) explicitly enumerated (s) and also allows, but does not require, the presence of other element (s) not enumerated (s). In addition to this broad meaning, as used here, the term "comprising" also encompasses the limiting meaning "consisting of", according to which only the element (s) explicitly enumerated (s) and no other is present. In addition, the term "comprising" also includes the meaning of "consisting essentially of", which means that other element (s) may be present in addition to those explicitly enumerated (s) , provided that the element (s) present does not additionally alter (s) the technical effect achieved by the element (s) explicitly listed (s).

[0017] As used herein, the term "about" when referring to a particular value, for example, one end or ends of a range, encompasses and describes, in addition to the value specifically enumerated, a certain variation around the value specifically listed. Such variation may, for example, result from normal measurement variability, for example, in the weighing or distribution of various substances by methods known to the person skilled in the art. The term "about" should be understood as encompassing and describing a range of variability above and below a specified specific value, said percentage values being relative to the specific enumerated value itself, as follows. The term “about” can encompass and reveal ± 5.0% variability. The term “about” can cover and reveal a variability of ± 4.9%. The term “about” can cover and reveal a variability of ± 4.8%. The term “about” can cover and reveal a variability of ± 4.7%. The term “about” can cover and reveal a variability of ± 4.6%. The term “about” can cover and reveal a variability of ± 4.5%. The term “about” can encompass and reveal ± 4.4% variability. The term “about” can cover and reveal a variability of ± 4.3%. The term “about” can cover and reveal a variability of ± 4.2%. The term “about” can encompass and reveal ± 4.1% variability. The term “about” can cover and reveal a variability of ± 4.0%. The term “about” can cover and reveal a variability of ± 3.9%. The term “about” can encompass and reveal ± 3.8% variability. The term “about” can cover and reveal variability of ± 3.7%. The term “about” can cover and reveal a variability of ± 3.6%. The term “about” can encompass and reveal ± 3.5% variability. The term “about” can encompass and reveal variability of ± 3.4%. The term “about” can cover and reveal a variability of ± 3.3%. The term “about” can cover and reveal a variability of ± 3.2%. The term “about” can encompass and reveal ± 3.1% variability. The term “about” can cover and reveal a variability of ± 3.0%. The term “about” can encompass and reveal ± 2.9% variability. The term “about” can encompass and reveal ± 2.8% variability. The term “about” can cover and reveal a variability of ± 2.7%. The term “about” can encompass and reveal ± 2.6% variability. The term “about” can encompass and reveal ± 2.5% variability. The term “about” can encompass and reveal ± 2.4% variability. The term “about” can encompass and reveal ± 2.3% variability. The term “about” can encompass and reveal ± 2.2% variability. The term “about” can encompass and reveal ± 2.1% variability. The term “about” can encompass and reveal ± 2.0% variability. The term “about” can cover and reveal variability of ± 1.9%. The term "about" can encompass and reveal variability of ± 1.8%. The term “about” can cover and reveal a variability of ± 1.7%. The term “about” can cover and reveal a variability of ± 1.6%. The term “about” can encompass and reveal ± 1.5% variability. The term "about" can encompass and reveal variability of ± 1.4%. The term “about” can encompass and reveal ± 1.3% variability. The term “about” can encompass and reveal ± 1.2% variability. The term "about" can encompass and reveal variability of ± 1.1%. The term “about” can encompass and reveal ± 1.0% variability. The term “about” can encompass and reveal ± 0.9% variability. The term “about” can cover and reveal a variability of ± 0.8%. The term “about” can cover and reveal a variability of ± 0.7%. The term “about” can encompass and reveal ± 0.6% variability. The term “about” can encompass and reveal ± 0.5% variability. The term “about” can encompass and reveal ± 0.4% variability. The term “about” can encompass and reveal ± 0.3% variability. The term "about" can encompass and reveal ± 0.2% variability. The term “about” can cover and reveal 0.1% variability. The term "about", in reference to the particular enumerated value, can encompass and describe that exact particular value itself, regardless of any explicit mention that that exact particular value is included; even in the absence of an explicit indication that the term "about" includes the particular exact enumerated value, that exact particular value is still included in the range created by the term "about" and is therefore described. Unless otherwise stated, if the term “about” is enumerated before the first end of a number range, this term refers to both the first end of the range and the second end of the range. For example, a range numbered "about X to Y" should read "about X to about Y". The same applies to an enumerated range of weight ratios. For example, an enumerated range of weight ratios of "about X: Y - A: B" should be read as a weight ratio of "(about X) :( about Y) - (about A): (about B) ".

[0018] Unless otherwise specified, the designation of a range in this application using a hyphen (“-“) that separates two values between parentheses X and Y, or two reasons between parentheses, should be understood as meaning and describing the specified range in which both the X and Y end values are included. The same applies to a range expressed as "from X to Y". Consequently, the expressions of ranges such as "XY", "X to Y" and "XY" should be understood equivalently as meaning and describing a range that covers the final value X, all values between X and Y, as well as the final value Y. On the other hand, the designation of a range in this application using the word "between" preceding two values and in brackets X and Y, or two reasons in brackets, should be understood as meaning and describing the specified range in which both X and Y end values are excluded, but all values between the specified X and Y end values are included.

[0019] As used herein, the term "composition" encompasses and describes any physical entity comprising or consisting or consisting essentially of the respective substances listed. The physical form of the composition is not restricted. For example, the term "composition" encompasses and describes a powder in which the listed substances are present in the form of a powder. As a further example, the term "composition" also encompasses and describes a liquid solution in which the listed substances are present in solubilized form. As an additional example, the term "composition" also encompasses and describes an emulsion in which the listed substances are present. As an additional example, the term "composition" also encompasses and describes a suspension in which the listed substances are present. In particular, the term "composition" can be a "pharmaceutical composition", as defined here below, and can be formulated for a desired route of administration. As used and described herein, the term "composition" can also be a composition suitable for oral delivery, for example, in the form of a tablet, including, but not limited to, an effervescent tablet or a multilayer tablet, a powder, for example , in the form of a sachet, a hard capsule, a soft gel capsule, a syrup, a cache, a lozenge lozenge or lozenge, a lozenge, for example, a gummy lozenge, an ointment or a liquid preparation. The term "composition" can also be a composition suitable for non-oral delivery, for example, in the form of a suppository, a tablet, a hard capsule, a soft gel capsule, a cream, a gel, a plaster or a liquid. Additional dosage forms of the composition, as well as said routes of administration, are shown here below.

[0020] As used here, the term "inositol" encompasses and describes the substance which has the chemical formula C6H12O6 and a structure according to any of the 9 known isomers of inositol, ie: Myo-inositol cilo-inositol muco-inositol D-chiro-inositol L-chiro-inositol Chiro-inositol Neo-inositol Alo-inositol Epi-inositol Cis-inositol

[0021] In a preferred embodiment of the present invention in any of the various aspects presented herein, inositol is myo-inositol. In another preferred embodiment of the present invention, in any of the various aspects presented herein, inositol is D-chiro-inositol. In another preferred embodiment of the present invention, in any of the various aspects presented herein, inositol is a mixture of myo-inositol and D-chiro-inositol in any weight ratio. The weight ratio of myo-inositol to D-chiro-inositol (myo-inositol: D-chiro-inositol) in a mixture of these can be advantageously from about 100: 1 to 10: 1, or it can be between 100: 1 and 10: 1, or it may be about 40: 1. It is understood that, in the case of a mixture of different types of inositol, the weight of "inositol", for example, in the sense of any of the weight reasons mentioned here, will be the sum of all types of inositol present.

[0022] As used herein, the term "alpha-lactalbumin" means and describes the known alpha-lactalbumin protein present in the milk of mammalian species. As such, it can be easily isolated from milk, in particular whey from various mammals, for example, from cow's milk, by established methods known to the person skilled in the art, for example, using chromatography / gel filtration, membrane separation , enzymatic hydrolysis, and precipitation / aggregation technologies (Kamau SM, Cheison SC, Chen W, Liu X, Lu R. Alpha-Lactalbumin: Its Production Technologies and Bioactive Peptides. Comprehensive reviews in food science and food safety, 2010, 9, 197-212). Various alpha-lactalbumin orthologists are also commercially available for purchase, for example, human alpha-lactalbumin and bovine alpha-lactalbumin. In particular, the "alpha-lactalbumin" of the present invention can be human alpha-lactalbumin (eg, human alpha-lactalbumin designated by CAS number 9013-90-5), bovine alpha-lactalbumin (e.g. bovine alpha-lactalbumin) under CAS number 9051-29-0), sheep alpha-lactalbumin, caprine alpha-lactalbumin, donkey alpha-lactalbumin, camel alpha-lactalbumin, horse alpha-lactalbumin, porcine alpha-lactalbumin, buffalo alpha-lactalbumin. Due to the wide availability and, therefore, the low cost, of cow's milk as a source of alpha-lactalbumin, bovine alpha-lactalbumin is particularly preferred. Also preferred is human alpha-lactalbumin, in the isolated form of human milk or in the recombinant form. Although human alpha-lactalbumin or recombinant human alpha-lactalbumin can be employed by any route of administration here, human alpha-lactalbumin or recombinant human alpha-lactalbumin is especially preferred if the route of administration of the inventive compositions or in the uses and inventive methods are intended to be parenteral, for example, by infusion.

[0023] The human alpha-lactalbumin precursor has 142 amino acids in the following sequence (NCBI accession number NP_002280; https://www.ncbi.nlm.nih.gov/protein/NP_002280):

[0024] MRFFVPLFLVGILFPAILAKQFTKCELSQLLKDIDGYGGIALPELICTMFH

TSGYDTQAIVENNESTEYGLFQISNKLWCKSSQVPQSRNICDISCDKFLDDDIT

DDIMCAKKILDIKGIDYWLAHKALCTEKLEQWLCEKL (SEQ ID NO: 1).

The 19 amino acid signal peptide at the N-terminus of SEQ ID NO: 1 is underlined in the above sequence. The mature form of human alpha-lactalbumin corresponds to amino acids 20 to 142 (inclusive) of SEQ ID NO: 1, that is, the portion of SEQ ID NO: 1 as shown above that is not underlined. For example, the following nucleic acid sequence (NCBI accession number NM_002289; https://www.ncbi.nlm.nih.gov/nuccore/NM_002289) encodes SEQ ID NO: 1 above and can be used in the production of recombinant human alpha-lactalbumin: (SEQ ID NO: 2).

[0026] The bovine alpha-lactalbumin precursor has 142 amino acids in the following sequence (NCBI accession number NP_776803; https://www.ncbi.nlm.nih.gov/protein/NP_776803):

[0027] MMSFVSLLLVGILFHATQAEQLTKCEVFRELKDLKGYGGVSLPEWVCT

TFHTSGYDTQAIVQNNDSTEYGLFQINNKIWCKDDQNPHSSNICNISCDKFLD

DDLTDDIMCVKKILDKVGINYWLAHKALCSEKLDQWLCEKL (SEQ ID NO: 3)

The 19 amino acid signal peptide at the N-terminus of SEQ ID NO: 3 is underlined in the above sequence. The mature form of bovine alpha-lactalbumin corresponds to amino acids 20 to 142 (inclusive) of SEQ ID NO: 3, that is, the portion of SEQ ID NO: 3 as shown above that is not underlined. For example, the following nucleic acid sequence (NCBI accession number NM_174378; https://www.ncbi.nlm.nih.gov/nuccore/NM_174378)

encodes SEQ ID NO: 3 above and can be used in the production of recombinant bovine alpha-lactalbumin: (SEQ ID NO: 4).

[0029] The sheep alpha-lactalbumin precursor has 142 amino acids in the following sequence (NCBI accession number NP_001009797; https://www.ncbi.nlm.nih.gov/protein/NP_001009797)

[0030] MMSFVSLLLVGILFHATQAEQLTKCEAFQKLKDLKDYGGVSLPEWVCT

AFHTSGYDTQAIVQNNDSTEYGLFQINNKIWCKDDQNPHSRNICNISCDKFLD

DDLTDDIVCAKKILDKVGINYWLAHKALCSEKLDQWLCEKL (SEQ ID NO: 5)

The 19 amino acid signal peptide at the N-terminus of SEQ ID NO: 5 is underlined in the above sequence. The mature form of bovine alpha-lactalbumin corresponds to amino acids 20 to 142 (inclusive) of SEQ ID NO: 5, that is, the portion of SEQ ID NO: 5 as shown above that is not underlined. For example, the following nucleic acid sequence (NCBI accession number NM_001009797; https://www.ncbi.nlm.nih.gov/nuccore/NM_001009797) encodes SEQ ID NO: 5 above and can be used in the production of recombinant ovine alpha-lactalbumin:

[0032] (SEQ ID NO: 6)

[0033] The porcine alpha-lactalbumin precursor has 141 amino acids in the following sequence (NCBI accession number NP_999525; https://www.ncbi.nlm.nih.gov/protein/NP_999525):

[0034] MMSFVSLLVVGILFPAIQAKQFTKCELSQVLKDMDGYGDITLPEWICTIF

HISGYDTKTIVHDNGSTEYGLFQINNKLWCRDNQIQSKNICGISCDKFLDDDLT

DDMMCAKKILDNEGIDYWLAHKALCSEKLDQWLCEKM (SEQ ID NO: 7) The 19 amino acid signal peptide at the N-terminus of SEQ ID NO: 7 is underlined in the above sequence. The mature form of porcine alpha-lactalbumin corresponds to amino acids 20 to 141 (inclusive) of SEQ ID NO: 7, that is, the portion of SEQ ID NO: 7 as shown above that is not underlined. For example, the following nucleic acid sequence (NCBI accession number

NM_214360; https://www.ncbi.nlm.nih.gov/nuccore/NM_214360) encodes SEQ ID NO: 7 above and can be used in the production of recombinant porcine alpha-lactalbumin: (SEQ ID NO: 8).

[0035] The caprine alpha-lactalbumin precursor has 142 amino acids in the following sequence (NCBI accession number NP_001272564; https://www.ncbi.nlm.nih.gov/protein/NP_001272564):

[0036] MMSFVSLLLVGILFHATQAEQLTKCEVFQKLKDLKDYGGVSLPEWVCT

AFHTSGYDTQAIVQNNDSTEYGLFQINNKIWCKDDQNPHSRNICNISCDKFLD

DDLTDDIVCAKKILDKVGINYWLAHKALCSEKLDQWLCEKL (SEQ ID NO: 9)

The 19 amino acid signal peptide at the N-terminus of SEQ ID NO: 9 is underlined in the above sequence. The mature form of alpha-lactalbumin caprine corresponds to amino acids 20 to 142 (inclusive) of SEQ ID NO: 9, that is, the portion of SEQ ID NO: 9 as shown above that is not underlined. For example, the following nucleic acid sequence (NCBI accession number NM_001285635; https://www.ncbi.nlm.nih.gov/nuccore/NM_001285635) encodes SEQ ID NO: 9 above and can be used in the production of recombinant goat alpha-lactalbumin: (SEQ ID NO: 10)

[0038] The buffalo alpha-lactalbumin precursor has 142 amino acids in the following sequence (NCBI accession number NP_001277865; https://www.ncbi.nlm.nih.gov/protein/NP_001277865):

[0039] MMSFVSLLLVGSLFHATQAEQLTKCEVFRELRDLKDYGGVSLPEWVC

TAFHTSGYDTQAIVQNNDSTEYGLFQINNKIWCKDDQNPHSSNICNISCDKFLD

DDLTDDIMCVKKILDKVGINYWLAHKALCSEKLDQWLCEKL (SEQ ID NO: 11)

The 18 amino acid signal peptide at the N-terminus of SEQ ID NO: 11 is underlined in the above sequence. The mature form of buffalo alpha-lactalbumin corresponds to amino acids 19 to 142 (inclusive) of SEQ ID NO: 11, that is, the portion of SEQ ID NO: 11 as shown above that is not underlined. For example, the following nucleic acid sequence (NCBI accession number NM_001290936; https://www.ncbi.nlm.nih.gov/nuccore/NM_001290936) encodes SEQ ID NO: 11 above and can be used in the production of recombinant buffalo alpha-lactalbumin: (SEQ ID NO: 12).

[0041] As used here, the term "source of folate" or grammatically related terms, such as "source of folate", means any compound that, when introduced into the body, provides a source of folate to the body. One of these sources of folate is folic acid, which has the accepted definition in the technique of the compound of chemical formula C19H19N7O6 called N- (4 - {[(2-amino-4-oxo-1,4-dihydropteridin) - 6-yl) methyl] amino} benzoyl) -L-glutamic (IUPAC designation (2S) -2 - [[4 - [(2-amino-4-oxo-1H-pteridin-6-yl) methylamino] benzoyl] amino] pentanedioic) and has the chemical structure:

[0042] A source of folate can also be folate itself, for example, in one of the salt forms of deprotonated folic acid. Another suitable source of folate is 5-methyltetrahydrofolate.

[0043] As used herein, the term "weight ratio", as it applies to the relative amounts of two substances in the composition, for example, denotes the ratio of the weight of one compound to the weight of another compound in the respective composition. In particular, the weight ratio does not take into account the weight of any fillers, excipients, diluents, etc. which, in addition to the substances for which the weight ratio is specified, may also be present in the composition. As a particular non-binding example, a composition comprising an 8: 1 inositol: alpha-lactalbumin weight ratio denotes a composition in which, by weight, the amount of inositol exceeds that of alpha-lactalbumin by a factor of 8,

regardless of the weight of any additional fillers, excipients, thinners, etc. that may be present in the composition. In case the composition issue is anything other than a solid composition, a specified weight ratio belongs to the amounts by weight of components in that composition in their corresponding solid form, before solubilization, emulsification, suspension, etc. in the composition in question.

[0044] Although the present application mentions discrete realizations, it should be understood that any realization and the characteristics contained therein can be freely combined with any other realization and the characteristics contained therein, even in the absence of an explicit declaration for that purpose. Such combinations of one embodiment with another, or one or more characteristics in any embodiment with one or more characteristics in any other embodiment, thus belong to the description of the present application as filed as understood by the person skilled in the art. Compositions Comprising Inositol and Alpha-Lactalbumin

[0045] When addressing the problem of providing improved compositions, uses and methods to alleviate medical conditions, such as infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, or to relieve PCOS or anovulation itself, inventors have surprisingly found that the advantageous effect due to the administration of inositol, for example, only with myo-inositol or in mixture with D-chiro-inositol, can be increased by the combined administration with alpha-lactalbumin. For example, as described here and shown in the following examples, plasma levels of inositol in the blood, for example, myo-inositol, are higher after their combined administration with alpha-lactalbumin than after the administration of inositol, for example myo-lactalbumin. inositol, without alpha-lactalbumin. Although not limited by theory, the inventors believe that the increased plasma level of inositol, for example, myo-inositol, may be due to increased transfer through the intestinal wall in the presence of alpha-lactalbumin. In view of this, the composition may preferably be a composition suitable for oral delivery, for example, in the form of a tablet, including, but not limited to, an effervescent or multilayer tablet; a powder, for example, a sachet; a hard capsule; a soft gel capsule; a syrup; a fee; a change; an “ozenge” tablet; or a liquid preparation.

[0046] The surprising discovery that the combined administration of alpha-lactalbumin with inositol has important therapeutic advantages in the treatment and prevention of infertility and subfertility, especially infertility and subfertility caused by PCOS or anovulation, or the treatment and prevention of PCOS or the anovulation itself. For example, while many patients with infertile, subfertile, anovulatory PCOS respond well to treatment with myo-inositol alone, a subset of these patients remains resistant to treatment with myo-inositol alone. It is important to note that the present inventors have found that the combined administration of inositol, for example, myo-inositol, together with alpha-lactalbumin can effectively treat resistant patients who have not responded to inositol monotherapy. In this sense, the present invention allows the recovery of infertility, subfertility, anovulation or PCOS in patients who, with existing therapies, would remain recalcitrant and intractable. This has the final effect of broadening the scope of treatment and preventing infertility, subfertility, anovulation and PCOS in women of childbearing age to an extent previously impossible.

[0047] Thus, an aspect of the present invention provides a composition which comprises, consists essentially of or consists of inositol and alpha-lactalbumin, in which inositol and alpha-lactalbumin are present in the composition in a respective weight ratio of about 1: 1 to 50: 1. In one embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 1: 1 and 50: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 8: 1 to 50: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 8: 1 and 50: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 20: 1 to 48: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 20: 1 and 48: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 25: 1 to 46: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 25: 1 and 46: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 28: 1 to 45: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 28: 1 and 45: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 30: 1 to 44: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 30: 1 and 44: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 33: 1 to 43: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 33: 1 and 43: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 35: 1 to 42: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 35: 1 and 42: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 37: 1 to 41: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 37: 1 and 41: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 39: 1 to 41: 1. In another embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio between 39: 1 and 41: 1. In another especially preferred embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of about 40: 1. In another especially preferred embodiment, inositol and alpha-lactalbumin are present in the composition of the invention in a respective weight ratio of 40: 1. It should be understood that each of the above weight ratios and weight ratio ranges belong to the amounts of inositol and alpha-lactalbumin whose composition of the invention may comprise, consist essentially of, or consist of.

[0048] The person skilled in the art will understand that the "composition" is intended to be used to treat or prevent certain pathological conditions, as defined herein. The composition can also be used to treat physiological conditions in which a higher intake of inositol is desirable. Consequently, the composition of the invention can, therefore, be in a corresponding medicinal form, i.e., a pharmaceutical composition. According to the compositions provided for the treatment or prevention of pathological conditions in the prior art, the person skilled in the art will therefore understand that the inventive composition itself is not a food or drink, that is, it is not itself a product that would otherwise be consumed for sustenance. In particular, the inventive composition itself will not be a food or drink product (for example, it will not be a dairy product, for example, a product based on bovine milk, such as a product based on whey, or it will not be a food bar, for example a food bar containing grains), although such food products and drinks are described and covered as separate aspects of the present invention distinct from the inventive composition per se.

[0049] Various types of inositol and alpha-lactalbumin have been defined above. A combination of myo-inositol and alpha-lactalbumin in any of the above weight ratios is especially preferred. A combination of D-chiro-inositol and alpha-lactalbumin in any of the above weight ratios is also preferred. A mixture of myo-inositol, D-chiro-inositol and alpha-lactalbumin is also preferred, where the weight of inositol belongs to the combined weight of myo-inositol and D-chiro-inositol. In these compositions comprising both myo-inositol and D-chiro-inositol as being "inositol", the respective weight ratio of myo-inositol and D-chiro-inositol (myo-inositol: D-chiro-inositol) can be about from 10: 1 to 100: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be between 10: 1 and 100: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be from about 20: 1 to 80: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be between 20: 1 and 80: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be from about 30: 1 to 60: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be between 30: 1 and 60: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be from about 35: 1 to 50: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be between 35: 1 and 50: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be about 40: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be 40: 1.

[0050] It is understood that the establishment of a certain amount of inositol in the inventive composition is sufficient to automatically establish a corresponding amount of alpha-lactalbumin in the inventive composition, according to the above weight ratios of inositol: alpha-lactalbumin. Adherence to the weight ratios of inositol: alpha-lactalbumin presented above ensures that the composition of the invention can achieve an advantageous technical effect in the treatment or prevention of infertility or subfertility, especially infertility or subfertility caused by PCOS or anovulation, or in the treatment or in the prevention of PCOS or anovulation itself. However, the inventors have found that the provision of a certain minimum amount of inositol in the inventive composition can be advantageous in ensuring that the desired therapeutic or prophylactic effect can be achieved in a reasonable number of administrations. Typically, successful treatment of infertility or subfertility, especially infertility or subfertility caused by PCOS or anovulation, as well as successful treatment of PCOS or anovulation itself, for example, so that previously absent ovulation is restored, it can be achieved by daily administration of up to about 6000 mg of inositol or about 4000 mg of inositol. Certainly, daily administration of this amount of inositol can be achieved using any composition adhering to the weight ratios of inositol: alpha-lactalbumin, as described above, the only difference between compositions of different weight ratios of inositol: alpha-lactalbumin, being the how often such a composition should be administered to achieve a certain daily target amount of inositol. However, from the point of view of the impact of any repeated administration on the patient's quality of life, it may be advantageous to guarantee a minimum amount of inositol in the composition, in order to correspondingly decrease the number of daily administrations necessary to achieve a certain daily target amount. of inositol, for example, the daily target amount of inositol indicated above.

[0051] Therefore, in certain embodiments, the composition of the invention can advantageously comprise up to about 6000 mg of inositol or about 500 to 4000 mg of inositol. The composition of the invention can also advantageously comprise between 500 and 4000 mg of inositol. The composition of the invention may also preferably comprise about 1000 to 3000 mg of inositol. The composition of the invention may also preferably comprise between 1000 and 3000 mg of inositol. In especially preferred embodiments, the composition of the invention comprises about 600 mg of inositol or about 2000 mg of inositol. In additional especially preferred embodiments, the composition of the invention comprises 600 mg of inositol or 2000 mg of inositol. Especially, the latest embodiments in which the composition of the invention comprises about 2000 mg of inositol, 2000 mg of inositol, about 3000 mg of inositol or 3000 mg of inositol, are especially advantageous because such compositions would need to be administered only twice a day to reach the daily target amount of about 6000 mg of inositol or 4000 mg of inositol. An inventive composition comprising about 2000 mg of inositol, in which the weight ratio of inositol: alpha-lactalbumin is, for example, about 8: 1-50: 1 or between 8: 1-50: 1, implies an amount corresponding alpha-lactalbumin range from about 40 to 250 mg, or between 40 to 250 mg, respectively. As mentioned above, a particularly advantageous weight ratio of inositol: alpha-lactalbumin is about 40: 1 which, assuming about 2000 mg of inositol, for example myo-inositol, in the inventive composition, implies about 50 mg of alpha -lactalbumin in the inventive composition. Thus, inventive compositions comprising about 2000 mg of inositol and about 50 mg of alpha-lactalbumin are especially preferred as they achieve an ideal balance between therapeutic efficacy and acceptable impact on the patient's quality of life.

[0052] Conversely, it is understood that the establishment of a certain amount of alpha-lactalbumin in the inventive composition is sufficient to automatically establish a corresponding amount of inositol in the inventive composition, according to the above weight ratios of inositol: alpha-lactalbumin. In one embodiment, the composition of the invention comprises from about 10 to 500 mg of alpha-lactalbumin. In another embodiment, the composition of the invention comprises between 10 and 500 mg of alpha-lactalbumin. In another embodiment, the composition of the invention comprises from about 20 to 100 mg of alpha-lactalbumin. In another embodiment, the composition of the invention comprises between 20 and 100 mg of alpha-lactalbumin. In another embodiment, the composition of the invention comprises from about 30 to 70 mg of alpha-lactalbumin. In another embodiment, the composition of the invention comprises between 30 and 70 mg of alpha-lactalbumin. In another embodiment, the composition of the invention comprises about 50 mg of alpha-lactalbumin. In another embodiment, the composition of the invention comprises 50 mg of alpha-lactalbumin. Assuming an inositol: alpha-lactalbumin ratio of about 40: 1, a composition comprising about 50 mg of alpha-lactalbumin implies about 2000 mg of inositol, for example, myo-inositol, in the same composition. The inventive compositions comprising about 2000 mg of inositol, for example, myo-inositol and about 50 mg of alpha-lactalbumin are therefore especially preferred for the reasons given above.

[0053] As presented above, the inositol in the inventive composition can be any one or more of the 9 isomers of inositol, in particular myo-inositol, D-chiro-inositol or a mixture of these in any ratio by weight of any one, particularly those presented here above. Preferably, alpha-lactalbumin is human or bovine alpha-lactalbumin. In an especially preferred embodiment, the inventive composition comprises human myo-inositol and human alpha-lactalbumin in a respective 40: 1 weight ratio, for example, about 2000 mg of myo-inositol and about 50 mg of human alpha-lactalbumin . In an especially preferred further embodiment, the composition of the invention comprises myo-inositol and bovine alpha-lactalbumin in a respective weight ratio of 40: 1, for example, about 2000 mg of myo-inositol and about 50 mg of alpha- bovine lactalbumin.

[0054] The compositions of the invention may further comprise a source of folate, preferably folic acid, i.e., N- (4 - {[(2-amino-4-oxo-1,4-dihydropteridin-6- il) methyl] amino} benzoyl) -L-glutamic. The addition of a source of folate, preferably folic acid, to the inventive composition can be advantageous, in view of the known importance of folate in the gestation process, in particular in preventing deformations such as spina bifida. Considering the beneficial effect of the inventive composition in the treatment or prevention of infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, as well as in the treatment or prevention of PCOS or anovulation itself, the inventive composition is likely to be taken by women of childbearing age who tried unsuccessfully to conceive in order to promote the desired pregnancy.

In this case, having an accumulated storage of folate is advantageous for an adequate pregnancy in the expected subsequent pregnancy.

In the broadest sense, then, the inclusion of a source of folate, preferably folic acid, in the inventive composition supports the downstream process that the inventive composition ultimately promotes.

However, the source of folate, preferably folic acid, is not necessarily necessary to prevent or treat infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, nor is it necessary to prevent or treat PCOS or anovulation itself. .

In fact, several controlled clinical studies related to the treatment of PCOS were carried out using folic acid as a placebo and determined that no specific effects attributable to folic acid were found in the selected population (see, for example, Costantino D, Minozzi G, Minozzi E, Guaraldi Ç.

Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial.

Eur Rev Med Pharmacol Sci 2009; 13: 105–10; Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM.

Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome.

Gynecol Endocrinol. 2008; 24: 139–44; and Gerli S, Papaleo E, Ferrari A, Di Renzo GC.

Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS.

Eur Rev Med Pharmacol Sci 2007; 11: 347–54). Consequently, the technical effect described here related to the treatment of infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, as well as related to the treatment of PCOS or anovulation itself, can be obtained with inositol and alpha-lactalbumin in double combination in isolation,

without a source of folate, for example, folic acid.

[0055] In one embodiment, the inventive composition comprises a source of folate, preferably folic acid, in a respective weight ratio of the source of alpha-lactalbumin: folate from about 1: 0.001 to 1: 0.01. In another embodiment, the weight ratio of alpha-lactalbumin: folate source is about 1: 0.001 and 1: 0.01. In another embodiment, the weight ratio of alpha-lactalbumin: folate source is about 1: 0.002 to 1: 0.008. In another embodiment, the weight ratio of alpha-lactalbumin: folate source is between 1: 0.002 to 1: 0.008. In another embodiment, the weight ratio of alpha-lactalbumin: folate source is about 1: 0.003 to 1: 0.006. In another embodiment, the weight ratio of alpha-lactalbumin: folate source is between 1: 0.003 to 1: 0.006. In another embodiment, the weight ratio of alpha-lactalbumin: folate source is about 1: 0.004.

[0056] In another embodiment, the weight ratio of alpha-lactalbumin: folate source is 1: 0.004. It is understood that the specific type of inositol in the inventive composition can be any of the isomers of inositol or mixtures thereof presented above. For example, in a preferred embodiment of the invention, the composition comprises about 2000 mg of inositol, about 50 mg of alpha-lactalbumin and about 200 µg of folic acid. In an especially preferred embodiment of the invention, the composition comprises about 2000 mg of myo-inositol, about 50 mg of human alpha-lactalbumin and about 200 µg of folic acid. In another especially preferred embodiment of the invention, the composition comprises 2000 mg of myo-inositol, 50 mg of human alpha-lactalbumin and 200 µg of folic acid. In another especially preferred embodiment of the invention, the composition comprises about 2000 mg of myo-inositol, about 50 mg of bovine alpha-lactalbumin and about 200 µg of folic acid. In another especially preferred embodiment of the invention, the composition comprises 2000 mg of myo-inositol, 50 mg of bovine alpha-lactalbumin and 200 µg of folic acid.

[0057] As described above, the inventive composition itself is intended for final use in the treatment or prevention of certain pathological conditions. The composition can also be used to treat physiological conditions where a higher intake of inositol is desirable. As such, it will generally be manufactured according to the processes established for the manufacture of pharmaceutical products. Consequently, in one embodiment, the inventive composition is a pharmaceutical composition. The compositions of the invention, including pharmaceutical compositions, can further comprise at least one pharmaceutically acceptable ingredient. Although the inventive composition, including the pharmaceutical composition, can itself be administered to an individual, it should be understood that the addition of one or more pharmaceutically acceptable ingredients in addition to inositol and alpha-lactalbumin can be advantageous in making the composition more suitable for direct administration to an individual by a given predetermined route. Consequently, the inventive composition, including a "pharmaceutical composition", can be formulated to comprise, in addition to inositol and alpha-lactalbumin, a pharmaceutically acceptable ingredient that makes the composition more suitable or especially suitable for direct administration to an individual by a given route , without further exams. This suitability can belong to several different routes of administration, including oral, parenteral, transmucosal, transurethral, transrectal, vaginal or perivaginal, topical, transdermal or intravesical, as further presented below. Where present, such ingredients, as well as their beneficial impact on the suitability of the inventive composition for different routes of administration, are presented below. a) Formulation of the Inventive Composition for Adequacy to Oral Distribution

[0058] A composition of the invention suitable for oral distribution can be prepared, packaged or sold in the form of a discrete solid dose unit including a sachet (for example, a powder in a sachet), a tablet, a hard or soft capsule, a cache, a trocisco or a lozenge lozenge, each containing a predetermined amount of inositol and alpha-lactalbumin in a ratio as specified here. Other formulations suitable for oral delivery include a powder or granular formulation, an aqueous or oily suspension, an aqueous or oily solution or an emulsion. As used here, an "oily" liquid comprises a liquid molecule containing carbon that exhibits a less polar character than water.

[0059] It is especially preferred that the discrete solid dose unit of the inventive composition is in the form of a powder, especially presented in the form of a sachet. As used herein, the term "sachet" refers to a sealed pouch containing the inventive composition. The bag can be made of paper, wax paper, laminated paper or a combination of paper and aluminum. The material from which the sachet is formed is preferably impermeable to ambient humidity and other potential atmospheric contaminants, so that, when sealing said sachet, the inventive composition in the form of a powder contained therein remains in a free flow form until the use.

[0060] A tablet comprising inositol and alpha-lactalbumin can, for example, be manufactured by compressing or molding inositol and alpha-lactalbumin, optionally with one or more additional ingredients. The compressed tablets can be prepared by pressing, in a suitable device, inositol and alpha-lactalbumin in a free flowing form, such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent and a dispersing agent. Molded tablets can, for example, be made by molding, in a suitable device, a mixture of inositol and alpha-lactalbumin, a pharmaceutically acceptable carrier and at least enough liquid to moisten the mixture.

[0061] Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surface active agents include, but are not limited to, sodium lauryl sulfate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pregelatinized corn starch, polyvinylpyrrolidone and hydroxypropylmethylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica and talc.

[0062] The tablets may be uncoated or may be coated using known methods to achieve delayed disintegration in an individual's gastrointestinal tract, thereby providing the sustained release and absorption of inositol and alpha-lactalbumin. After ingestion, the composition of the invention will be advantageously released before passage to the small intestine, where the primary reabsorption of inositol occurs. For example, a material such as glyceryl monostearate or glyceryl distearate can be used to coat tablets. The tablets may also comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative or some combination thereof, in order to provide a pharmaceutically attractive and palatable preparation.

[0063] Hard capsules comprising inositol and alpha-lactalbumin can be prepared using a physiologically degradable composition, such as gelatin or cellulose derivatives. Such hard capsules comprise inositol and alpha-lactalbumin and may further comprise additional ingredients, including, for example, an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin.

[0064] Soft gelatin capsules comprising inositol and alpha-lactalbumin can be prepared using a physiologically degradable composition, such as gelatin combined with a plasticizer (i.e., glycerol) as the basic component of the soft gelatin shell. Soft gelatin capsules may contain a liquid or semi-solid solution, suspension or microemulsion pre-concentrate. The filling of the soft capsule comprises inositol and alpha-lactalbumin, which can be mixed with water or an oil medium, such as peanut oil, liquid paraffin, olive oil, soy oil, sunflower oil, a lecithin, such as, for example, soy lecithin or sunflower lecithin, medium chain triglycerides, polyglycerol oleate, beeswax, fatty acid mono and diglycerides, or combinations of any of the above.

[0065] Liquid formulations of the composition of the invention that are especially suitable for oral distribution can be prepared, packaged and sold in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle before ingestion.

[0066] Liquid suspensions can be prepared using conventional methods to achieve the suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils, such as peanuts, olives, sesame or coconut oil, fractionated vegetable oils and mineral oils, such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients, including, but not limited to, suspending agents, dispersing agents or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, tragacanth gum, acacia gum and cellulose derivatives, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing agents or wetting agents include, but are not limited to, naturally occurring phosphatides, such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived a fatty acid and a hexitol or with a partial ester derived from a fatty acid and a hexitol anhydride (for example, polyoxyethylene stearate, heptadecaethylene-oxycethanol, polyoxyethylene sorbitol mono-oleate and polyoxyethylene sorbitan mono-oleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl or n-propyl parahydroxybenzoates, ascorbic acid and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin and cetyl alcohol.

[0067] Powder and granular formulations of a composition, for example, a pharmaceutical composition of the invention, can be prepared using known methods. Such formulations can be administered directly to an individual, used, for example, to form sachets or tablets, fill the capsules or prepare an aqueous or oily suspension or solution by adding an aqueous or oily carrier therein. Each of these formulations can further comprise one or more dispersing or wetting agents, a suspending agent and a preservative. Additional excipients, such as fillers and sweeteners, flavorings, or coloring agents, can also be included in these formulations.

[0068] The composition of the invention can also be prepared, packaged or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oily phase can be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents, such as naturally occurring gums, such as acacia or tragacanth gum, naturally occurring phosphatides, such as soy phosphate or lecithin, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides, such as sorbitan monooleate and condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsions can also contain additional ingredients, including, for example, sweetening or flavoring agents.

[0069] Methods for impregnating or coating a material with a chemical composition are known in the art and include, but are not limited to, methods for depositing or bonding a chemical composition to a surface, methods for incorporating a chemical composition into the structure of a material during the synthesis of the material (for example, as with a physiologically degradable material) and methods of absorbing an aqueous or oily solution or suspension in an absorbent material, with or without subsequent drying. b) Formulation of the Inventive Composition to Suit Parenteral Administration

[0070] For parenteral administration, the composition of the invention comprising inositol and alpha-lactalbumin can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for bolus dose administration and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other agents, such as suspending, stabilizing and / or dispersing agents, such as those mentioned above, can be used.

[0071] When formulating the composition of the invention for parenteral administration to an individual, it may be advantageous to provide alpha-lactalbumin in the form of human alpha-lactalbumin, for example, recombinant human alpha-lactalbumin, as explained here above. In this way, one can minimize the risk of triggering unwanted immunogenic reactions in the individual against non-human protein substances.

[0072] The composition of the invention comprising inositol and alpha-lactalbumin can be made especially suitable for parenteral administration by formulation with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations can be prepared, packaged or sold in a form suitable for bolus or continuous administration. Injectable formulations can be prepared, packaged or sold in unit dosage form, such as in ampoules, crushed or not, or in multi-dose containers containing a preservative. Compositions especially suitable for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes and implantable sustained release or biodegradable formulations. Such compositions may further comprise one or more additional ingredients, including, but not limited to, suspending, stabilizing or dispersing agents. In an embodiment of the inventive composition that is especially suitable for parenteral administration, the active ingredient is provided in dry form (for example, powder or granular) for reconstitution with a suitable vehicle (for example, sterile pyrogen-free water) prior to administration parenteral composition of the reconstituted composition.

[0073] The inventive composition can be prepared, packaged or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution can be formulated according to the known technique and can comprise, in addition to the active ingredient, additional ingredients, such as the dispersing agents, wetting agents or suspending agents described herein. Such sterile injectable compositions can be prepared using a non-toxic, parenterally acceptable diluent or solvent, such as water or 1,3-butanediol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution and fixed oils, such as synthetic mono or diglycerides. Other usual parenterally administered formulations include those that comprise the active ingredient in microcrystalline form, in a liposomal preparation or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials, such as an emulsion, an ion exchange resin, a sparingly soluble polymer or a sparingly soluble salt. c) Formulation of the Inventive Composition to Suit Transmucosal Administration

[0074] The inventive composition comprising inositol and alpha-lactalbumin can be formulated to be suitable for transmucosal administration. The formulation can include any substances or dosage unit suitable for application to mucosal tissue. For example, the selected active agent can be administered to the oral mucosa in a patch, tablet or plaster, administered sublingually by placing a solid dosage form under the tongue, administered lingually by placing a solid dosage form on the tongue, administered nasally as droplets or a nasal spray, a non-aerosol liquid formulation or a dry powder, placed in or near the rectum ("transretal" formulations) or administered to the urethra as a suppository, ointment or similar. d) Formulation of the Inventive Composition to Suit Transuretal Administration

[0075] The inventive composition comprising inositol and alpha-lactalbumin can also be formulated to be suitable for transuretal administration. In this case, the inventive composition may comprise a urethral dosage form containing the active agent and one or more selected vehicles or excipients, such as water, silicone, waxes, petroleum jelly, polyethylene glycol ("PEG"), propylene glycol ("PG"), liposomes, sugars, such as mannitol and lactose / and / or a variety of other materials. A transurethral permeation enhancer can be included in the dosage form. Examples of suitable permeation enhancers include dimethyl sulfoxide ("DMSO"), dimethyl formamide (" DMF "), N, N-dimethylacetamide (" DMA "), decylmethylsulfoxide (" C10 MSO "), polyethylene glycol monolaurate (" PEGML "), glycerol monolaurate, lecithin, the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecyl-cyclazacyclo-heptan-2-one, surfactants as discussed above, including, for example, TWEEN-80 ™ and lower alkanols, such as ethanol e) Formulation of the Inventive Composition for Suitability for Transretal Administration

[0076] The inventive composition comprising inositol and alpha-lactalbumin can also be formulated to be suitable for transrectal administration. Transrectal dosage forms can include rectal suppositories, creams, ointments and liquid formulations (enemas). The suppository, cream, ointment or liquid form for transrectal delivery comprises inositol and alpha-lactalbumin and one or more conventional non-toxic vehicles suitable for administration of transrectal drugs. The transrectal dosage forms of the inventive composition can be manufactured using conventional processes. The transrectal dosing unit can be manufactured to disintegrate quickly or over a period of several hours. The time to complete disintegration can be in the range of about 10 minutes to about 6 hours, for example, less than about 3 hours. f) Formulation of the Inventive Composition to Suit Vaginal or Perivaginal Administration

[0077] The inventive composition comprising inositol and alpha-lactalbumin can also be formulated to be especially suitable for vaginal or perivaginal administration. Dosage forms suitable for this purpose may include vaginal suppositories, creams, ointments, liquid formulations, pessaries, tampons, gels, pastes, foams or sprays. The suppository, cream, ointment, liquid formulation, pessary, buffer, gel, paste, foam or spray for vaginal or perivaginal delivery comprises a therapeutically effective amount of the selected active agent and one or more conventional non-toxic vehicles suitable for vaginal drug delivery or perivaginal. The vaginal or perivaginal forms of the present invention can be manufactured using conventional procedures, as, for example, described in Remington: The Science and Practice of Pharmacy, supra. The vaginal or perivaginal dosing unit can be manufactured to disintegrate quickly or over a period of several hours. The time to complete disintegration can be in the range of about 10 minutes to about 6 hours, for example, less than about 3 hours. g) Formulation of the Inventive Composition to Suit Topical Formulations

[0078] The inventive composition comprising inositol and alpha-lactalbumin can also be formulated to be especially suitable for topical administration. Dosage forms suitable for that purpose may include any form suitable for application to the body surface and may comprise, for example, an ointment, cream, gel, lotion, solution, paste or the like, and / or may be prepared in a manner containing liposomes, micelles and / or microspheres. In certain embodiments, the topical formulations here are ointments, creams and gels. h) Formulation of the Inventive Composition to Suit Transdermal Administration

[0079] The inventive composition comprising inositol and alpha-lactalbumin can also be formulated to be especially suitable for transdermal administration. As is known to the person skilled in the art, transdermal administration involves the distribution of pharmaceutical compounds through percutaneous passage of the compound in the patient's systemic circulation. This can be affected, for example, by transdermal patches or iontophoresis devices. Components other than inositol and alpha-lactalbumin can also be incorporated into transdermal patches. For example, transdermal compositions and / or patches can be formulated with one or more preservatives or bacteriostatic agents,

including, but not limited to, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride and the like. Dosage forms of the inventive composition for topical administration of inositol and alpha-lactalbumin may include creams, sprays, lotions, gels, ointments, eye drops, nose drops, ear drops and the like. In such dosage forms, the ingredients of the inventive composition can be mixed to form a white, smooth, homogeneous, opaque cream or lotion with, for example, 1% or 2% (w / w) benzyl alcohol as a preservative, emulsifying wax , glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution. In addition, the compositions may contain polyethylene glycol 400. They can be mixed to form ointments with, for example, 2% benzyl alcohol (w / w) as a preservative, white petrolatum, emulsifying wax and tenox II (butylated hydroxyanisol, propyl gallate) , citric acid, propylene glycol). Fabric pads or rolls of bandage material, for example, gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or the like can also be used for topical application. The compositions can also be applied topically using a transdermal patch, such as one from an acrylic-based polymer plaster with a resinous crosslinking agent impregnated with the composition and laminated on an impermeable support.

[0080] Examples of suitable skin contact plasters include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes and the like. Alternatively, the reservoir containing the drug and the skin contact patch are separate and distinct layers, with the patch underlying the reservoir which, in this case, can be a polymeric matrix as described above, or a liquid or hydrogel reservoir, or take some the other way. i) Formulation of the Inventive Composition to Suit the Intravesical Administration

[0081] The term intravesical administration is used here in its conventional sense to mean the distribution of a drug directly in the bladder. Suitable methods for intravesical administration can be found, for example, in US Patent Nos. 6,207,180 and 6,039,967. Therapeutic Uses and Methods

[0082] As described herein, the inventors have discovered that the therapeutic effect of inositol in the treatment or prevention of infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, or in the treatment or prevention of PCOS or anovulation and by you itself, is increased by co-administration of alpha-lactalbumin. The inventors are not aware of any therapeutic or prophylactic use of inositol and alpha-lactalbumin together in the same regimen, let alone for any of the purposes indicated above.

[0083] Thus, an additional aspect of the invention provides a combination of inositol and alpha-lactalbumin for the use of a medicament. Inositol can be chosen from the types of inositol and mixtures of inositol presented above. Alpha-lactalbumin is as defined above. As explained above, the combination of inositol and alpha-lactalbumin in the same regimen has the surprising effect of extending the known therapeutic effect of inositol to individuals who would otherwise remain resistant only to inositol therapy.

[0084] As used here, the term "combination", or the expression "in combination with" with reference to inositol and alpha-lactalbumin, refers to the coupling of inositol and alpha-lactalbumin for the purpose of its co-administration to an individual within a given treatment regime. A given treatment regimen typically comprises multiple repeated co-administrations of inositol and alpha-lactalbumin over a predetermined period of time, for example, more than 1 month, more than 2 months, more than 3 months, more than 4 months or more than 5 months or more, a period of at least 3 months being preferred. Co-administration of inositol and alpha-lactalbumin can be repeated several times a day, for example, once, twice, 3 times, 4 times, 5 times or more, a repetition about twice a day being preferred. That is, the co-administration of inositol and alpha-lactalbumin is repeated for a predetermined period of time, and the sum of the cases of co-administration for that predetermined period of time constitutes the prophylactic or therapeutic regimen.

[0085] The coupling of inositol and alpha-lactalbumin understood as a "combination" of these two substances does not need to be physical, nor does it imply simultaneous administration. The reference to a "combination" of inositol and alpha-lactalbumin, therefore, covers and describes multiple possibilities in relation to the route and the time of administration of the respective substances. Covered and described in the meaning of "combination" is, for example, the coupling of inositol and alpha-lactalbumin for simultaneous administration by the same route, simultaneous administration by different routes, chronologically staggered administration by the same route or chronologically staggered administration by different routes. Any of the administration routes described above can be combined in any way, although it is generally preferable that the route is oral. Especially preferable is the simultaneous administration of inositol and alpha-lactalbumin by the oral route, for example, when inositol and alpha-lactalbumin are present in a composition, for example, in one of the inventive compositions presented here, for example, in the form of a tablet , hard capsule, soft gel capsule or powder, for example, in the form of a sachet, for ingestion.

[0086] The simultaneous administration of inositol and alpha-lactalbumin by the same route can, for example, take the form of inositol and alpha-lactalbumin being comprised in the same physical composition, this composition being administered, for example, ingested by the individual, so that inositol and alpha-lactalbumin enter the body via the same route, for example, orally, at the same time. The coupling of inositol and alpha-lactalbumin for staggered administration in a given co-administration, therefore, is also possible, and is also covered and described in the term "combination". The order of administration of alpha-lactalbumin and inositol is not particularly important; chronologically staggered administration of inositol and alpha-lactalbumin may include previous administration of alpha-lactalbumin and subsequent administration of inositol, or previous administration of inositol and subsequent administration of alpha-lactalbumin. For example, staggered administration of inositol and alpha-lactalbumin by the same route may take the form of initial oral distribution of alpha-lactalbumin, followed by oral distribution of inositol; the coupling of inositol and alpha-lactalbumin in this way falls within the meaning of, and is described by, "combination", as used herein. On the other hand, the phased administration of inositol and alpha-lactalbumin by different routes may take the form of initial oral distribution of alpha-lactalbumin, followed by the administration of inositol, for example, rectal or vaginal suppository; the coupling of inositol and alpha-lactalbumin in this manner also falls within the meaning of, and is described by, "combination", as used herein.

[0087] There are no particular restrictions on the length of time between the administration of inositol and alpha-lactalbumin, in the event that the co-administration is chronologically staggered; however, it will generally be more effective and convenient when any interval between the administration of inositol and alpha-lactalbumin is short, approaching simultaneity, for example, in the order of minutes. In rare cases, this interval can extend up to an hour or several hours between the respective administrations. The inventors observed that prolonged intake of alpha-lactalbumin improves the bioavailability of inositol, in particular myo-inositol, even after 12 hours. In rare cases, then, if the co-administration of inositol and alpha-lactalbumin is staggered chronologically, the interval between administrations in some cases can be up to 12 hours. However, even if inositol and alpha-lactalbumin are administered chronologically in a staggered manner, either by this or by different routes, the term “combination” means that a given co-administration of both, inositol and alpha-lactalbumin, in any regime will be completed, that is, both substances will be administered at the time when the next co-administration of inositol and alpha-lactalbumin (which in itself can be again simultaneous or chronologically staggered by this or by different routes) within the same occurrences of regime.

[0088] In certain embodiments, the combination of inositol and alpha-lactalbumin involves a combination in a respective weight ratio of inositol: alpha-lactalbumin of about 1: 1-50: 1, or any of the other respective weight ratios or weight ratio ranges presented above for the inventive composition itself. It should be understood that each of these weight ratios and weight ratio ranges belong to the amounts of inositol and alpha-lactalbumin whose combination can comprise, consist essentially of or consist of.

[0089] In one embodiment, in the combination of inositol and alpha-lactalbumin for use as a medicine, inositol is chosen from myo-inositol, D-chiro-inositol or a mixture of these in any weight ratio. In a further embodiment, in the combination of inositol and alpha-lactalbumin for use as a medicament, the combination is in the form of a composition of the invention as described above, that is, a composition comprising inositol and alpha-lactalbumin, in which inositol and alpha -lactalbumin are present in a respective weight ratio of about 1: 1-50: 1 of inositol: alpha-lactalbumin. In a further embodiment, in the combination of inositol and alpha-lactalbumin for use as a medicine, the combination is in the form of a composition of the invention, as described above, in any of its embodiments.

[0090] A further aspect of the invention provides inositol for use in a method of treating or preventing infertility or subfertility, in particular infertility or subfertility caused by polycystic ovary syndrome (PCOS) or anovulation, in an individual, wherein the method comprises administer inositol to the individual in combination with alpha-lactalbumin. In a related aspect, the invention provides inositol, for use in a method of treating or preventing polycystic ovary syndrome (PCOS) or anovulation in an individual, wherein the method comprises administering inositol to the individual in combination with alpha-lactalbumin. The term “combination” must be understood in the sense explained above.

[0091] A further aspect of the invention provides inositol for use in a method of treating or preventing infertility or subfertility, in particular infertility having its origin in idiopathic infertility, in an individual, wherein the method comprises administering inositol to the individual in combination with alpha-lactalbumin. In a related aspect, the invention provides inositol for use in a method of treating or preventing idiopathic infertility in an individual, wherein the method comprises administering inositol to the individual in combination with alpha-lactalbumin. The term “combination” must be understood in the sense explained above.

[0092] A further aspect of the invention provides a use of inositol in combination with alpha-lactalbumin in the manufacture of a medicament for the treatment or prevention of infertility or subfertility, in particular infertility or subfertility caused by polycystic ovary syndrome (PCOS) or anovulation. In a related aspect, the invention provides a use of inositol in combination with alpha-lactalbumin in the manufacture of a medicament for the treatment or prevention of polycystic ovary syndrome (PCOS) or anovulation. The term “combination” must be understood in the sense explained above.

[0093] An additional aspect of the invention provides a use of inositol in combination with alpha-lactalbumin in the manufacture of a medicament for the treatment or prevention of infertility or subfertility, in particular infertility having its origin in idiopathic infertility. In a related aspect, the invention provides a use of inositol in combination with alpha-lactalbumin in the manufacture of a medicament for the treatment or prevention of idiopathic infertility. The term “combination” must be understood in the sense explained above.

[0094] A further aspect of the invention provides a method of treating or preventing infertility or subfertility, in particular a method of treating or preventing infertility or subfertility caused by polycystic ovary syndrome (PCOS) or anovulation in an individual who needs or potentially it requires this, in which the method comprises administering a therapeutically or prophylactically effective amount of inositol to the individual in combination with alpha-lactalbumin. In a related aspect, the invention provides a method of treating or preventing polycystic ovary syndrome (PCOS) or anovulation in an individual who needs or potentially needs it, wherein the method comprises administering a therapeutic or prophylactically effective amount of inositol to the individual in combination with alpha-lactalbumin. The term “combination” must be understood in the sense explained above.

[0095] An additional aspect of the invention provides a method of treating or preventing infertility or subfertility, in particular a method of treating or preventing infertility having its origin in idiopathic infertility, in an individual who needs or potentially needs it, where the The method comprises administering a therapeutically or prophylactically effective amount of inositol to the individual in combination with alpha-lactalbumin. In a related aspect, the invention provides a method of treating or preventing idiopathic infertility in an individual who needs or potentially needs it, wherein the method comprises administering a therapeutic or prophylactically effective amount of inositol to the individual in combination with alpha-lactalbumin. The term “combination” must be understood in the sense explained above.

[0096] As used here, the term "infertility" and grammatically related terms, such as "infertile", describe a pathological state in which, despite repeated attempts over a long period of pregnancy,

no pregnancies have been reached. Normally, an individual, who is a woman of childbearing age, who is "infertile" has not become pregnant, despite repeated attempts to conceive, over a period of time, for example, about 1 year. An individual who is "infertile" does not normally become pregnant without medical assistance, for example, therapeutic intervention. Although infertility can have its origin in any of the sexes, the infertility referred to here is understood as female infertility, affecting a female of childbearing age.

[0097] As used here, the term "subfertility" and grammatically related terms, such as "subfertile", describe a pathological state in which attempts to conceive have a chance of success, although this pregnancy usually takes longer to achieve than than in normal individuals, that is, about 6 months. "Subfertility" is, therefore, the condition of being less than normally fertile, although it is still able to achieve pregnancy. Typically, then, an individual, who is a woman of childbearing age, who is "sub-fertile" will usually need about 6 months of repeated attempts to get pregnant, but still usually gets pregnant within 6 months to a year of trying. Although subfertility can have its origin in any of the genders, the subfertility referred to here is understood as female subfertility, affecting a female person of childbearing age.

[0098] As used here, the term "idiopathic infertility" and grammatically related terms, such as "idiopathically infertile", is considered a pathological state in which, despite repeated attempts over a long period to become pregnant, no pregnancy has been achieved. Normally, an individual, who is a woman of childbearing age, who suffers from “idiopathic infertility” did not become pregnant, despite repeated attempts to conceive, for a period of, for example, about 12 months (ie, inability to conceive after 12 months of unprotected sex). An individual who is "idiopathically infertile" does not normally get pregnant without medical assistance, for example, therapeutic intervention. Although idiopathic infertility can have its origin in any of the genders, idiopathic infertility referred to here is understood as female idiopathic infertility, affecting a female of childbearing age. The term "idiopathic infertility", as used herein, is understood to be a subclass of infertility. For the purposes of this invention, a woman with an inability to conceive, as above, suffers from "idiopathic infertility" when, in addition to the observed inability to conceive, she has a negative test for each of the following: hyperprolactinemia, hypothyroidism, Cushing's syndrome, adrenal hyperplasia, obesity, polycystic ovary syndrome (PCOS) and anovulation.

[0099] Certainly, it is not always immediately apparent whether the cause of a pregnancy failure is due to infertility or subfertility. From the point of view of a woman of childbearing age trying to conceive, the only thing initially observed is that the desired pregnancy is not achieved immediately. A failure to conceive after a month or two may, of course, be due simply to chance, and after just that period of time the individual has no way of knowing whether the observed failure to conceive will persist for many months. The classification of a woman of childbearing age as "sub-fertile" or "infertile", therefore, will normally only be possible after a certain period of six months or twelve months, respectively, when it is clear that the failure to carry out the pregnancy is not due by chance, but it can have other pathological causes. At this point, such suspected pathological causes can still be investigated.

[0100] As used here, the term "anovulation" refers to a state in which the ovaries do not release an oocyte. Therefore, ovulation does not occur. Anovulation can be caused by multiple factors, such as PCOS, excessive stress, excessive exercise, hormonal imbalance or any combination of these factors. "Anovulation", which is a cause of subfertility or infertility treated by the present invention, or which can be treated by the present invention, will not be an anovulation due to genetic abnormalities, such as Turner's syndrome, physical deformities in the female reproductive system or factors normal physiological conditions, such as menopause.

[0101] As used here, the term "oligo-ovulation" refers to a state in which ovulation is irregular or infrequent, but not completely absent.

[0102] As used here, "polycystic ovary syndrome" (PCOS) denotes a condition in which 2 of the following 3 diagnostic features are present: clinical or biochemical hyperandrogenism, chronic anovulation (or oligo-ovulation) and polycystic ovaries. These diagnostic criteria correspond to the consensus criteria presented during the Rotterdam consensus workshop group ESHRE-ASRM in 2003. Although PCOS is diagnosed when 2 of the 3 criteria above are met, PCOS treatment in the sense of the present invention will abolish all the 3 observable criteria mentioned above. Thus, the treatment of PCOS in the sense of the present invention abolishes anovulation.

[0103] As used here, the term "treat" or grammatically related variants thereof, such as "treatment", "treating" etc. it means the improvement, even if temporarily, covering, but not demanding the complete abolition of a pathological state. In the broadest sense, the treatment of infertility or subfertility, by the medical uses and treatment methods mentioned here, means achieving a pregnancy following a treatment regimen as specified here, in which previous attempts to achieve pregnancy without applying such medical uses and methods treatment failed to result in the desired pregnancy. "Treatment" of PCOS means the at least temporary improvement or abolition of the three diagnostic criteria for PCOS, as described here. "Treatment" of anovulation means at least temporary improvement or abolition of anovulation, so that ovulation occurs at least once. "Treatment" of idiopathic infertility means the improvement or at least temporary abolition of the criteria for diagnosing idiopathic infertility, as defined here,

preferably so that biochemical pregnancy, as determined by a positive test for human chorionic gonadotropin (beta hCG), is achieved, for example, 14 days after ovulation.

[0104] As used here, the term "prevent" and grammatically related terms, such as "prevent", "prevention" etc., refer to scenarios in which the medical uses and methods of treatment described here are applied to prevent possible, suspected or expected occurrence of infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, or PCOS or anovulation itself. Such a suspicion that PCOS may be present may derive (even in the absence of a corresponding diagnosis) from the known frequency of PCOS as the observed cause of infertility or subfertility, for example, in the case where infertility or subfertility has been determined, but before a medical diagnosis of PCOS. Such suspicion or expectation that PCOS may be present may also derive from past experiences, for example, if an individual was successful in getting pregnant for the first time, but had difficulties in doing so, and trying to get pregnant a second or more times . In such a case, the individual would have prior knowledge, from his previous pregnancy, that he is predisposed to infertility or subfertility, or even that he has or is predisposed to contract PCOS and, therefore, would be justified in the expectation of similar difficulties experienced when trying to get pregnant a second or more times. In this case, the object of the invention can be applied before, together or in advance and together with attempts to get pregnant a little longer, so that the difficulties previously encountered are avoided. It will be understood that infertility or subfertility, especially infertility or subfertility caused by PCOS or anovulation, or PCOS or anovulation itself, may represent the normal physiological state of an individual, whose therapeutic intervention, for example, with the object of the present invention, needs just relieve it temporarily to create a window of increased fertility during which the desired pregnancy can be carried out. After the desired pregnancy is achieved with the present invention, the individual may, in the future, revert or suspect a reversion to their normal physiological state of infertility or subfertility (for example, associated with PCOS or associated with anovulation), or PCOS, to suggest that each subsequent attempt to become pregnant should be preceded, accompanied, or preceded and accompanied by the object of the present invention. Such scenarios are within the meaning of "prevention", as used here. Also within the definition of "prevention", as used here, is the administration of inositol and alpha-lactalbumin to an individual before any diagnosis of infertility or subfertility, or before any diagnosis of PCOS or anovulation.

[0105] Equivalent considerations, as described above, apply to the “prevention” of infertility that has its origin in idiopathic infertility or to the prevention of idiopathic infertility itself.

[0106] As used here, the phrase "caused by", for example, as in "infertility or subfertility caused by PCOS or anovulation" denotes an at least partial causal relationship between PCOS or anovulation on the one hand and, on the other hand, infertility or subfertility. For example, PCOS can cause anovulation, which in turn causes infertility or subfertility. In this case, there would be a causality between PCOS and anovulation, as well as between PCOS and anovulation, on the one hand, and, on the other hand, infertility or subfertility. In another example, an individual may be anovulatory, but not due to PCOS; this could, for example, be the case when excessive stress or hormonal imbalances or excessive exercise cause anovulation in the absence of PCOS. In such a scenario, a causality would exist between anovulation and infertility or subfertility. In yet another example, PCOS in an individual may be the direct cause of infertility or subfertility due to metabolic and hormonal abnormalities present in PCOS, in the absence of anovulation, that is, in cases where ovulation is normal despite a positive diagnosis of PCOS (for example, when an individual is positive for hyperandrogenism and polycystic ovaries, but still ovulates). In that case, there would be a direct causality between PCOS and infertility or subfertility, and no causality between PCOS and anovulation or anovulation and infertility or subfertility, with anovulation being absent. In all of the above scenarios, the main single or partial causes of infertility or subfertility, that is, PCOS, anovulation or PCOS and anovulation, are treated or avoided. In doing so, infertility or subfertility, which is the ultimate consequence of PCOS and / or anovulation, is also treated or prevented simultaneously.

[0107] As used here, the phrase "originating in", for example, as in "infertility having its origin in idiopathic infertility" denotes an etiological relationship between idiopathic infertility, on the one hand, and infertility, on the other. This is the situation when a patient who is considered infertile has been diagnosed as "idiopathically infertile" according to the definition here.

[0108] As used here, the term "individual" means an individual of the female sex. As the compositions, uses and methods of the invention relate in the broadest sense to achieve pregnancy, it will be understood that the female individual is a pre-menopausal female of childbearing age. The terms "individual" and "patient" are used interchangeably here.

[0109] The following achievements apply equally to the above inositol for use in combination with alpha-lactalbumin, to the above uses of inositol in combination with alpha-lactalbumin and to the above methods of treatment or prevention presented above.

[0110] In one embodiment, inositol and alpha-lactalbumin are administered in combination with the individual in a non-simultaneous manner within a given combined administration of a given regimen. As used here, the term "not simultaneously" means that inositol and alpha-lactalbumin are administered in a chronologically staggered manner, that is, at different times. Administration refers to a respective co-administration of inositol and alpha-lactalbumin within a broader treatment or prophylaxis regime. One embodiment involves administering inositol to the individual before administering alpha-lactalbumin to the individual. Another embodiment involves administering inositol to the individual after administering alpha-lactalbumin to the individual. It is understood that such non-simultaneous administration denotes any respective instance of co-administration of inositol and alpha-lactalbumin within the broader context of the general treatment regimen. As mentioned here, regardless of the order of administration, that is first inositol and second alpha-lactalbumin, or vice versa, the respective combined administration of inositol and alpha-lactalbumin can be by this or by different routes.

[0111] In an additional embodiment, inositol is administered to the individual simultaneously with alpha-lactalbumin. As mentioned above, the simultaneous administration of inositol and alpha-lactalbumin can be carried out by this or by different routes. More typically, it will be more advantageous and convenient to carry out the simultaneous administration of inositol and alpha-lactalbumin by the same route, preferably by an oral route. This will generally be accomplished by combining inositol and alpha-lactalbumin in the same composition, for example, in the form of a tablet, including, but not limited to, an effervescent tablet, a powder (especially presented in the form of a sachet), a hard capsule, a soft gel capsule, a syrup, a cache, a trocisco or a lozenge lozenge.

[0112] In additional embodiments, inositol and alpha-lactalbumin are administered in combination in respective weight ratios specific from inositol to alpha-lactalbumin (inositol: alpha-lactalbumin). In one embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio (inositol: alpha-lactalbumin) of about 1: 1 to 50: 1. In one embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 1: 1 and 50: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 8: 1 to 50: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 8: 1 and 50: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 20: 1 to 48: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 20: 1 and 48: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 25: 1 to 46: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 25: 1 and 46: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 28: 1 to 45: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 28: 1 and 45: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 30: 1 to 44: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 30: 1 and 44: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 33: 1 to 43: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 33: 1 and 43: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 35: 1 to 42: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 35: 1 and 42: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 37: 1 to 41: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 37: 1 and 41: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 39: 1 to 41: 1. In another embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio between 39: 1 and 41: 1. In another especially preferred embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of about 40: 1. In another especially preferred embodiment, inositol and alpha-lactalbumin are administered in a respective weight ratio of 40: 1. It should be understood that each of these weight ratios and weight ratio ranges belong to the amounts of inositol and alpha-lactalbumin whose combination can comprise, consist essentially of or consist of.

[0113] Various types of inositol and alpha-lactalbumin have been defined above. In the above clinical uses and methods, a combination of myo-inositol and alpha-lactalbumin in any of the above weight ratios is especially preferred. A combination of D-chiro-inositol and alpha-lactalbumin in any of the above weight ratios is also preferred. A mixture of myo-inositol, D-chiro-inositol and alpha-lactalbumin is also preferred, where the weight of inositol belongs to the combined weight of myo-inositol and D-chiro-inositol. In these compositions comprising both myo-inositol and D-chiro-inositol as being "inositol", the respective weight ratio of myo-inositol and D-chiro-inositol (myo-inositol: D-chiro-inositol) can be about from 10: 1 to 100: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be between 10: 1 and 100: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be from about 20: 1 to 80: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be between 20: 1 and 80: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be from about 30: 1 to 60: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be between 30: 1 and 60: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be from about 35: 1 to 50: 1. The respective weight ratio of myo-inositol and D-chiro-inositol can also be between 35: 1 and 50: 1. Especially preferred, the respective weight ratio of myo-inositol and D-chiro-inositol can also be about 40: 1 or it can be 40: 1.

[0114] Adherence to the weight ratios of inositol: alpha-lactalbumin presented above ensures that the composition of the invention can achieve an advantageous technical effect in the treatment or prevention of infertility or subfertility, especially infertility or subfertility caused by PCOS or anovulation,

or in the treatment or prevention of PCOS or anovulation itself. The inventors have found that the provision of a certain minimum amount of inositol in the inventive composition can be advantageous in ensuring that the desired therapeutic or prophylactic effect can be achieved in a reasonable number of administrations. Typically, the successful treatment or prevention of infertility or subfertility, especially infertility or subfertility caused by or associated with PCOS, as well as the successful treatment or prevention of PCOS itself, for example, so that ovulation previously absent is restored, it can be achieved by daily administration of a total of about 6000 mg of inositol or about 4000 mg of inositol. Certainly, a variable number of combined administrations of inositol and alpha-lactalbumin may be necessary to achieve a given daily administration target of inositol, depending on the amount of inositol that was administered in either case. However, from the point of view of the impact of any such repeated administration on the patient's quality of life, it may be advantageous to guarantee a minimum amount of inositol in the composition, in order to correspondingly decrease the number of daily administrations necessary to achieve a given target quantity of inositol, for example, the target amount of inositol indicated above.

[0115] Therefore, certain realizations of the above medical uses and methods of treatment may advantageously comprise administration of about 6000 mg of inositol, or about 500 to 4000 mg of inositol, or between 500 and 4000 mg of inositol, in any administration combined. The above clinical uses and treatment methods may also preferably comprise administering from about 1000 to 3000 mg of inositol, or between 1000 and 3000 mg of inositol in any combination administration. The above clinical uses and treatment methods may also preferably comprise administering about 2000 mg of inositol, 2000 mg of inositol, about 3000 mg of inositol or 3000 mg of inositol, in any combination administration. Especially,

the latest achievements comprising administration of about 2000 mg of inositol, 2000 mg of inositol, about 3000 mg of inositol or 3000 mg of inositol, are especially advantageous because such combined administration would only be needed twice a day to achieve a target amount daily dose of about 6000 mg of inositol or about 4000 mg of inositol. A combined administration involving administration of about 2000 mg of inositol, in which the weight ratio of inositol: alpha-lactalbumin administered is, for example, about 8: 1-50: 1 or between 8: 1-50: 1, implies a corresponding amount of alpha-lactalbumin administered ranging from about 40 to 250 mg or between 40 to 250 mg, respectively. As mentioned above, a particularly advantageous weight ratio of inositol: alpha-lactalbumin is about 40: 1, which, assuming a combined administration involving administration of about 2000 mg of inositol, implies administration of about 50 mg of alpha-lactalbumin. Thus, combined administrations involving the administration of about 2000 mg of inositol, for example, myo-inositol and about 50 mg of alpha-lactalbumin are especially preferred as finding an ideal balance between therapeutic efficacy and acceptable impact on the quality of life. patient's life.

[0116] Conversely, it is understood that the establishment of a certain amount of alpha-lactalbumin in the medical uses and treatment methods above is sufficient to automatically establish a corresponding amount of inositol, according to the above weight ratios of inositol: alpha- lactalbumin. The above clinical uses and treatment methods may also preferably comprise administering from about 10 to 500 mg of alpha-lactalbumin, or between 10 and 500 mg of alpha-lactalbumin. The above clinical uses and treatment methods may also preferably comprise administering from about 20 to 100 mg of alpha-lactalbumin, or between 20 and 100 mg of alpha-lactalbumin. The above clinical uses and treatment methods may also preferably comprise administering from about 30 to 70 mg of alpha-lactalbumin, or between 30 and 70 mg of alpha-

lactalbumin. The above clinical uses and treatment methods may also preferably comprise administering about 50 mg of alpha-lactalbumin, or 50 mg of alpha-lactalbumin. Assuming an inositol: alpha-lactalbumin ratio of about 40: 1, administration of about 50 mg of alpha-lactalbumin implies administration of about 2000 mg of inositol in the same example of combined administration. The medical uses and treatment methods as presented above that involve the administration of about 2000 mg of inositol, for example, myo-inositol and about 50 mg of alpha-lactalbumin, are therefore especially preferred for the reasons given above.

[0117] As shown above, inositol can be any one or more of the 9 isomers of inositol, in particular myo-inositol, D-chiro-inositol or a mixture of these in any weight ratio of any, in particular those presented up here. Preferably, alpha-lactalbumin is human alpha-lactalbumin or bovine alpha-lactalbumin. In an especially preferred embodiment, the above medical uses and treatment methods comprise the combined administration of myo-inositol and human alpha-lactalbumin in a respective weight ratio of 40: 1, for example, about 2000 mg of myo-inositol and about 50 mg of human alpha-lactalbumin. In another especially preferred embodiment, the medical uses and treatment methods above comprise the combined administration of myo-inositol and bovine alpha-lactalbumin in a respective weight ratio of 40: 1, for example, about 2000 mg of myo-inositol and about 50 mg of bovine alpha-lactalbumin.

[0118] An additional realization of the medical uses and treatment methods above further comprises administering a source of folate, preferably folic acid, to the individual in combination with inositol and alpha-lactalbumin. Folic acid is understood to denote the N- (4 - {[(2-amino-4-oxo-1,4-dihydropteridin-6-yl) methyl] amino} benzoyl) -L-glutamic acid compound. The term "combination", as used in reference to folic acid, inositol and alpha-lactalbumin, should be understood analogously, as explained above, for the same term in reference to inositol and alpha-lactalbumin alone.

The addition of a source of folate, preferably folic acid, to the combination of administered substances can be advantageous, in view of the known importance of folic acid in the pregnancy process, in particular in the prevention of defects such as spina bifida.

Considering the beneficial effect of the above medical uses and treatment methods in the treatment or prevention of infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, as well as in the treatment or prevention of PCOS or anovulation itself, the individual in question will be a woman of childbearing age who tried to conceive without success and who wants to promote

In this case, having an accumulated storage of folate is advantageous for an adequate pregnancy in the expected subsequent pregnancy promoted by the medical uses and methods contained herein.

In the broadest sense, then, the combined administration of inositol, alpha-lactalbumin and folic acid supports the downstream process that the inventive uses and methods ultimately promote.

However, the source of folate, for example, folic acid, is not necessarily necessary to prevent or treat infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, nor is it necessary to prevent or treat PCOS or anovulation itself.

In fact, several controlled clinical studies related to the treatment of PCOS were carried out using folic acid as a placebo and determined that no specific effects attributable to folic acid were found in the selected population (see, for example, Costantino D, Minozzi G, Minozzi E, Guaraldi Ç.

Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial.

Eur Rev Med Pharmacol Sci 2009; 13: 105–10; Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM.

Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome.

Gynecol Endocrinol. 2008; 24: 139–44; and Gerli S, Papaleo E, Ferrari A, Di

Renzo GC. Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. Eur Rev Med Pharmacol Sci 2007; 11: 347–54). Consequently, the technical effect described here related to the treatment of infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, as well as related to the treatment of PCOS or anovulation itself, can be obtained with inositol and alpha-lactalbumin in double combination alone, without a source of folate, for example, folic acid.

[0119] If folic acid is administered in combination with inositol and alpha-lactalbumin in the medical uses and therapeutic methods above, the amount by weight of a source of folate, preferably folic acid, in any administration will generally be much less than amount by weight of the other two substances. For example, in a combined administration of folate source with inositol and alpha-lactalbumin, the folate source can be administered in a respective weight ratio of alpha-lactalbumin: folate source of about 1: 0.001 to 1: 0.01. In another embodiment of combined administration of folate source with inositol and alpha-lactalbumin, the folate source can be administered in a respective weight ratio of alpha-lactalbumin: folate source between 1: 0.001 and 1: 0.01. In another embodiment of combined administration of folate source with inositol and alpha-lactalbumin, the folate source can be administered in a respective weight ratio of alpha-lactalbumin: folate source of about 1: 0.002 to 1: 0.008. In another embodiment of combined administration of folate source with inositol and alpha-lactalbumin, the folate source can be administered in a respective weight ratio of alpha-lactalbumin: folate source between 1: 0.002 to 1: 0.008. In another embodiment of combined administration of folate source with inositol and alpha-lactalbumin, the folate source can be administered in a respective weight ratio of alpha-lactalbumin: folate source of about 1: 0.003 to 1: 0.006. In another embodiment of combined administration of folate source with inositol and alpha-lactalbumin, the folate source can be administered in a respective weight ratio of alpha-lactalbumin: folate source between 1: 0.003 to 1: 0.006. In another embodiment of combined administration of folate source with inositol and alpha-lactalbumin, the folate source can be administered in a respective weight ratio of alpha-lactalbumin: folate source of about 1: 0.004. In another embodiment of combined administration of folate source with inositol and alpha-lactalbumin, the folate source can be administered in a respective weight ratio of alpha-lactalbumin: folate source of 1: 0.004.

[0120] For example, in one embodiment, the combined administration of inositol, alpha-lactalbumin and a source of folate, preferably folic acid, comprises the combined administration of about 2000 mg of inositol, about 50 mg of alpha-lactalbumin and about 200 µg of folic acid. It is understood that the specific type of inositol administered can be any of the isomers of inositol or mixtures thereof presented above. In particular, the combined administration of inositol, alpha-lactalbumin and folic acid may comprise administration of about 2000 mg of myo-inositol, about 50 mg of human alpha-lactalbumin and about 200 µg of folic acid. In an additional especially preferred embodiment, the combined administration of inositol, alpha-lactalbumin and folic acid may comprise the combined administration of 2000 mg of myo-inositol, 50 mg of human alpha-lactalbumin and 200 µg of folic acid. In particular, the combined administration of inositol, alpha-lactalbumin and folic acid may comprise the administration of about 2000 mg of myo-inositol, about 50 mg of bovine alpha-lactalbumin and about 200 µg of folic acid. In an additional especially preferred embodiment, the combined administration of inositol, alpha-lactalbumin and folic acid may comprise the combined administration of 2000 mg of myo-inositol, 50 mg of bovine alpha-lactalbumin and 200 µg of folic acid.

[0121] In an especially preferred embodiment of the medical uses and therapeutic methods presented above, inositol and alpha-lactalbumin are administered in combination in the form of a composition comprising inositol and alpha-lactalbumin, and optionally also a source of folate, preferably acid folic.

The combined administration of inositol and alpha-lactalbumin, optionally together with a source of folate, preferably folic acid, in a composition assumes that inositol and alpha-lactalbumin, and optionally the source of folate, preferably folic acid, are administered simultaneously and by the same route.

In an especially preferred embodiment, the composition is a composition according to the above invention, for example, a composition comprising inositol and alpha-lactalbumin, in which inositol and alpha-lactalbumin are present in a respective weight ratio of about 1 : 1-50: 1, between 1: 1-50: 1, about 8: 1-50: 1, between 8: 1-50: 1, about 30: 1-50: 1, between 30: 1- 50: 1, about 33: 1-43: 1, between 33: 1-43: 1, about 40: 1 or any other weight ratio of preferred inositol: alpha-lactalbumin described in any other embodiment associated with the inventive composition described above.

Any embodiment of the inventive composition, as shown above, can be used in the inventive medical uses and treatment methods presented above, and is described here in that context, in particular in relation to the various weight ratios between inositol: alpha-lactalbumin.

In particular, the inositol and alpha-lactalbumin administered in the composition can be in a respective weight ratio of about 40: 1 inositol: alpha-lactalbumin, optionally together with a folate source, preferably folic acid, in a respective weight ratio of the source of alpha-lactalbumin: folate of about 1: 0.004. In this embodiment, inositol is preferably myo-inositol and alpha-lactalbumin is preferably human or bovine alpha-lactalbumin.

In an especially preferred embodiment, the medical uses and treatment methods described above comprise the combined administration of about 2000 mg of myo-inositol, about 50 mg of human or bovine alpha-lactalbumin and, optionally, about 200 µg of acid folic acid in a single composition formulated for oral distribution, for example, in the form of a tablet, including, but not limited to, an effervescent tablet, a powder (for example, in the form of a sachet), a hard capsule, a capsule in soft gel, syrup, cachê, trocisco or lozenge lozenge. In an especially preferred embodiment, the above medical uses and treatment methods comprise the combined administration of about 2000 mg of myo-inositol, about 50 mg of human or bovine alpha-lactalbumin and, optionally, about 200 µg of folic acid powder (for example, in the form of a sachet) or soft gel capsule. In an additional especially preferred embodiment, the above medical uses and treatment methods comprise the combined administration of about 2000 mg of myo-inositol, about 50 mg of human or bovine alpha-lactalbumin and about 200 µg of powdered folic acid (for example, in the form of a sachet) or a soft gel capsule. Kits

[0122] A further aspect of the invention relates to a kit, for example, a kit of parts, comprising inositol in a first container and alpha-lactalbumin in a second container. The inositol in the first container can be any one of inositol or mixtures of inositol presented above, in particular myo-inositol, D-chiro-inositol or a mixture of myo-inositol and D-chiro-inositol in any weight ratio. In particular, a mixture of myo-inositol and D-chiro-inositol in the first container can be in any weight ratio, as shown above. Likewise, the alpha-lactalbumin in the second container can be human or bovine alpha-lactalbumin.

[0123] Both inositol and alpha-lactalbumin in the respective first and second kit containers can be formulated for any type of administration, as shown above. The routes of administration for which inositol and alpha-lactalbumin in the respective first and second kit containers can be formulated can be the same or different. In the event that the routes of administration for which inositol and alpha-lactalbumin in the respective first and second kit containers are formulated are the same, it is preferable that the route of administration is oral.

In that case, inositol and alpha-lactalbumin in the respective first and second kit containers can be formulated independently as a tablet, including, but not limited to, an effervescent or multilayer tablet, a powder (for example, in the form of a sachet ), a hard capsule, a soft gel capsule, a syrup, a cache, a lozenge or lozenge lozenge or a liquid preparation. The independent formulation of each of inositol and alpha-lactalbumin as a soft gel tablet, powder or capsule is preferred, with the formulation of each of inositol and alpha-lactalbumin as a powder or soft gel being especially preferred.

[0124] The kit can additionally comprise information related, for example, to the content and dosage of each of the components of the kit. This information can be in the form of a message printed on the outside of a box comprising the kit, in the form of a leaflet enclosed in a box containing the kit, or in the form of a printed Internet address for a web page which provides information, or additional information related, for example, to the contents, intended use, dosage regime or administration of the contents of the kit or any mixture thereof.

[0125] The amount of inositol and alpha-lactalbumin in the respective kit containers can be in any of the reasons by weight of inositol: alpha-lactalbumin shown above. In addition, the inositol in the first container can be myo-inositol, D-chiro-inositol or any mixture of these in any ratio, especially any of the myo-inositol: D-chiro-inositol weight ratios shown above.

[0126] In one embodiment, the kit further comprises a source of folate, preferably folic acid, which can be comprised in the first container, the second container, in both the first container and the second container, in a third container or in any combination of these. The source of folate is as defined above, and is preferably folic acid. Food Products and Beverages

[0127] In another aspect, the present invention relates to a food product or beverage comprising inositol and alpha-lactalbumin in which the weight ratio between inositol and alpha-lactalbumin (inositol: alpha-lactalbumin) is about 1: 1 to 50: 1. This means that the amount by weight of inositol in the food product or drink will be greater than the amount by weight of alpha-lactalbumin in the food product or drink. Inositol can be any one of inositol or the mixtures of inositol presented above, in particular myo-inositol, D-chiro-inositol or a mixture of myo-inositol and D-chiro-inositol in any weight ratio. In particular, a mixture of myo-inositol and D-chiro-inositol can be in any weight ratio, as shown above. Likewise, alpha-lactalbumin can be human or bovine alpha-lactalbumin.

[0128] As used here, the term "food product" refers to an ingestible substance that, at the temperature at which it is stored and ingested properly, is in solid or semi-solid form and will be chewed before swallowing.

[0129] As used here, the term "drink" refers to an ingestible substance that, at the temperature at which it is stored and ingested properly, is in a free flowing liquid form and will not be chewed before swallowing.

[0130] The food product can, in principle, be any food product that has been processed to comprise inositol and alpha-lactalbumin in the specified ratio. Examples of such food products include a food bar, such as a chocolate bar, granola bar, ice cream bar or energy bar; bubble gum; candy; a breath of mint; yogurt; an edible gel; a ready meal, for example, a freeze-dried ready meal; a spreadable; a pudding; or a processed fruit product, such as a fruit pack or a fruit stick. Examples of such drinks include fruit juice or drinks containing fruit juice, milk drinks, for example, drinks containing milk or buttermilk,

drinks containing whey and drinks containing yogurt, energy drinks, soft drinks, flavored water drinks, etc.

[0131] The food or drink product may comprise inositol and alpha-lactalbumin in any of the respective weight ratios given above. For example, the food product or beverage can comprise inositol and alpha-lactalbumin in a respective weight ratio (inositol: alpha-lactalbumin) of between 1: 1 and 50: 1, about 2: 1-50: 1, between 2 : 1 and 50: 1, about 3: 1-50: 1, between 3: 1 and 50: 1, about 4: 1-50: 1, between 4: 1 and 50: 1, about 5: 1 - 50: 1, between 5: 1 and 50: 1, about 6: 1-50: 1, between 6: 1 and 50: 1, about 7: 1-50: 1, between 7: 1 and 50: 1, about 8: 1-50: 1, between 8: 1 and 50: 1, about 30: 1-50: 1, between 30: 1 and 50: 1, about 33: 1-43: 1, between 33: 1 and 43: 1, about 40: 1 or any other preferred weight ratio of inositol: alpha-lactalbumin described in any other embodiment associated with other aspects of the above invention.

[0132] The food or drink product may comprise a minimum amount of inositol, a minimum amount of alpha-lactalbumin or a minimum amount of both inositol and alpha-lactalbumin, as shown above. For example, the food product or drink where the weight ratio of inositol to alpha-lactalbumin (inositol: alpha-lactalbumin) is about 1: 1 to 50: 1, or is any other weight ratio, as shown above , can comprise up to about 6000 mg of inositol, about 500-4000 mg of inositol, about 1000-3000 mg of inositol or about 600 mg or about 2000 mg of inositol. Likewise, the food product or drink in which the weight ratio of inositol to alpha-lactalbumin (inositol: alpha-lactalbumin) is about 1: 1-50: 1 can comprise about 10 to 500 mg of alpha- lactalbumin, about 20 to 100 mg of alpha-lactalbumin, about 30 to 70 mg of alpha-lactalbumin or about 50 mg of alpha-lactalbumin. Ideally, the food product or beverage will be presented as a discrete ingestible unit, so that ingesting a unit of the food product, for example, a food bar, or a beverage unit, for example, a beverage bottle, provides a minimal amount of inositol and alpha-lactalbumin which, alone or combined with the intake of other discrete edible units, will support any of the therapeutic objectives indicated above.

[0133] In a further embodiment, the food or drink product may further comprise a source of folate, preferably folic acid, which is defined as presented above.

[0134] In a particularly preferred embodiment, the food product or beverage comprises about 2000 mg of myo-inositol and about 50 mg of human or bovine alpha-lactalbumin and can additionally comprise about 200 µg of folic acid.

[0135] In the following, several examples are provided illustrating various embodiments of the present invention and the technical effects and advantages that it achieves. It should be understood that the following examples are presented for illustrative purposes only and do not limit the claimed invention. In fact, the person skilled in the art will be able to easily accomplish other achievements within the spirit and scope of the claimed invention, while achieving the technical advantages described.

Examples General

[0136] In the broadest sense, the present inventors have found that a combined administration of inositol, for example, myo-inositol and alpha-lactalbumin, for example, alpha-lactalbumin, reaches ovulation in women with PCOS, where ovulation does not it can be achieved by administering inositol, for example, only with myo-inositol. The combination of inositol and alpha-lactalbumin, for example, myo-inositol and alpha-lactalbumin, in a regimen to prevent or treat PCOS in female individuals who need it, therefore, allows the doctor to successfully treat PCOS in cases previously recalcitrant to the existing treatment of PCOS. The ultimate effect of the present invention is thus to expand the population of patients with PCOS who can benefit from treatment with inositol, for example, myo-inositol.

[0137] The present inventors have further discovered that a combined administration of inositol, for example, myo-inositol and alpha-lactalbumin, for example, alpha-lactalbumin, achieves biochemical pregnancy in women with idiopathic infertility, in which biochemical pregnancy cannot be achieved by administering inositol, for example, only with myo-inositol. The combination of inositol and alpha-lactalbumin, for example, myo-inositol and alpha-lactalbumin, in a regimen to prevent or treat idiopathic infertility in female individuals who need it, therefore, allows the doctor to successfully treat idiopathic infertility . The ultimate effect of the present invention is, therefore, to expand the population of patients with idiopathic infertility who can benefit from treatment with inositol, for example, myo-inositol.

[0138] Although not wishing to be bound by theory, the observed results suggest that the improved absorption of myo-inositol, when administered in combination, for example, in the same composition as alpha-lactalbumin, may be related to a beneficial change in the microbiota intestinal and / or a transporter effect, both effected by alpha-lactalbumin.

Example 1 Pharmacokinetic Evaluation in Healthy Individuals: Myo-inositol plus Alpha-lactalbumin

[0139] The present example describes a pharmacokinetic study that combines oral administration of myo-inositol and alpha-lactalbumin in healthy subjects. The study aims to determine whether the combination of myo-inositol and alpha-lactalbumin is able to increase the plasma level of myo-inositol above that observed after administration with myo-inositol alone.

[0140] The study involved 15 healthy volunteers, 6 men and 9 women. Subjects were assessed based on medical history, physical examination and laboratory screening, and individuals who were in poor general health were excluded. The volunteers were aged between 18 and 35 years, with a body mass index (BMI) ranging between 21 and 25 kg / m2.

[0141] Subjects received orally 6 g of myo-inositol in powder form and then, after a 7-day washout period, 6 g of myo-inositol and 150 mg of alpha-lactalbumin, also in powder form. The pharmacokinetic parameters (PK) were evaluated after the respective administrations with myo-inositol alone or in combination with alpha-lactalbumin, determining in each case the plasma concentration of myo-inositol at various times after the respective administration. Blood samples were collected by venipuncture at the pre-dose (moment 0) and at moments 30, 60, 90, 120, 180 and 300 min post-administration.

[0142] As indicated above, the study consisted of two different phases:

[0143] Phase I: 6 g of myo-inositol in powder form were administered.

[0144] Phase II: 6 g of myo-inositol + 150 mg of powdered alpha-lactalbumin were administered.

[0145] The two phases were separated by a washout period of seven days.

[0146] The quantification of myo-inositol was performed using gas chromatography - mass spectrometry (GCMS) analysis after extraction with organic solvent (methanol) and derivatization with 500 µL of methoxamine in pyridine for 30 minutes at 70 ° C.

[0147] Cmax and Tmax were obtained directly from the plasma concentration, while the area under the curve (AUC (0-300)) was calculated using the trapezoidal method in the period from 0 to 300 min (Purves A., Journal of Pharmacokinetics and Biopharmaceutics, 1992; 20 (3), 211-224). The data sets were compared using a t test and a p-value <0.05 was considered statistically significant.

Table 1: Pharmacokinetic parameters after oral administration of 6 g of powdered myo-inositol and 6 g of myo-inositol plus 150 mg of powdered alpha-lactalbumin.

Parameter Average (SD) 6 g of myo- 6 g of myo-inositol p-value of inositol + 150 mg of alpha- Δ% lactalbumin Cmax p <0.0001 29% (μmol / L) 98.00 (7) 127, 0 (10) Tmax (min) No 0% 180.0 (8) 180.0 (5) significant AUC (0-300) 23760 p <0.001 24% (3568) 29370 (4793)

[0148] All enrolled individuals completed the trial. The analysis of the measured plasma concentrations of myo-inositol produced interesting results in relation to the PK parameters of the two formulations, in relation to the plasma concentration resulting from myo-inositol.

[0149] The data showed the plasma concentration of myo-inositol resulting from the two phases of the study (Table 1). The data obtained are represented graphically in Figure 1 for the 2 phases of the study. As the data above indicates, and as can be clearly seen in the corresponding Figure 1, plasma concentrations of myo-inositol after administration of powder containing 6 g of myo-inositol and alpha-lactalbumin were significantly higher than after administration of 6 g of powdered myo-inositol. These results show that the administration of myo-inositol in combination with alpha-lactalbumin leads to a plasma concentration of myo-inositol significantly higher than that observed when administering with myo-inositol alone.

Example 2

Pharmacokinetic Evaluation in Healthy Individuals: Glucose plus Alpha-lactalbumin

[0150] The present study aims to determine whether the effect seen in Example 1 is specific to the combination of inositol and alpha-lactalbumin, for example, myo-inositol and alpha-lactalbumin. To evaluate this, the present inventors carried out a study using glucose instead of inositol (as polyols / carbohydrates, glucose and inositol have similar structures and the same molecular weight). Specifically, glucose was administered to individuals only, as well as in combination with alpha-lactalbumin, to see if alpha-lactalbumin increases glucose bioavailability in a manner similar to that seen in Example 1 above for myo-inositol.

[0151] The study involved 10 healthy volunteers, 5 men and 5 women. Subjects were assessed based on medical history, physical examination and laboratory screening, and individuals who were in poor general health were excluded. The volunteers were aged between 18 and 35 years, with a body mass index (BMI) ranging between 21 and 25 kg / m2.

[0152] The subjects received orally a 50% glucose solution (100 ml) and then, after a washout period of 7 days, the same solution plus 1200 mg of alpha-lactalbumin. To ensure comparability with the results of Example 1 above, the 50% glucose solution contained 50 g of glucose, and that amount was combined with 1200 mg of alpha-lactalbumin. This produced about the same ratio for glucose: alpha-lactalbumin used for myo-inositol: alpha-lactalbumin in Example 1. The pharmacokinetic parameters (PK) were evaluated after the respective glucose administrations alone or in combination with alpha-lactalbumin, in each case determining the concentration of glucose in the blood at various times after the respective administration. Blood samples were collected by capillary puncture at the pre-dose (moment 0) and at moments 30, 60, 120 and 180 minutes after administration.

[0153] As indicated above, the study consisted of two different phases:

[0154] Phase I: 50% glucose solution (100 ml) was administered.

[0155] Phase II: 50% glucose solution (100 ml) + 1200 mg of alpha-lactalbumin in tablet form was administered (via the same route; an alpha-lactalbumin tablet was swallowed simultaneously with the glucose solution).

[0156] The two phases were separated by a washout period of seven days.

[0157] Glucose quantification was performed using an Accu-Chek Active glucometer (Roche Diabetes Care GmbH). Cmax and Tmax were obtained directly from blood concentration, while the area under the curve (AUC (0- 180)) was calculated using the trapezoidal method over a period of 0 to 180 min (Purves A., Journal of Pharmacokinetics and Biopharmaceutics, 1992 ; 20 (3), 211-224). The data sets were compared using a t test and a p-value <0.05 was considered statistically significant.

Table 2: Pharmacokinetic parameters after oral administration of a 50% glucose solution and 50% glucose solution plus 1200 mg of alpha-lactalbumin tablet.

Parameter Average (SD) sol. 50% Glu value of p sol. 50% + alpha- Δ% Glu lactalbumin 1200 mg Cmax No -5% (mg / dL) 159.01 (21) 151.67 (32) significant Tmax (min) No 30.6 (12) 30.2 ( 7) 0% significant AUC (0-180) 21141 20555 (278) No -3% (153) significant

[0158] The results showed no significant difference in blood glucose levels in the two groups (Table 2). In fact, no statistical difference was shown between the two AUCs. This indicates that alpha-lactalbumin has no appreciable effect on another compound very similar to myo-inositol, suggesting that the advantageous effect observed for the combined administration of myo-inositol and alpha-lactalbumin is specific for that pair of substances.

Example 3 Clinical Evaluation in Women with PCOS

[0159] The present study aims to develop an effective therapy in women suffering from PCOS based on the improved absorption of inositol, for example, myo-inositol, when administered in combination with alpha-lactalbumin. Specifically, while the treatment of PCOS with only myo-inositol correlates with an improvement in the disease in a significant number of women, there are still women who still do not respond to treatment with myo-inositol alone. The present inventors have therefore sought to determine whether the higher level of myo-inositol absorption observed when administering myo-inositol in conjunction with alpha-lactalbumin can enable successful treatment of patients with PCOS who had previously not responded to treatment. with myo-inositol only. In that case, then the treatment of PCOS with inositol in combination with alpha-lactalbumin, for example, myo-inositol in combination with alpha-lactalbumin, would represent a significant therapeutic advance, allowing the treatment of PCOS in previously recalcitrant cases, thereby substantially expanding the therapeutic benefit of inositol, for example, myo-inositol, in the treatment of

SOP.

[0160] The present study included 20 patients with anovulatory PCOS.

[0161] The inclusion criteria were: age between 20 and 35 years; SOP according to the Rotterdam consensus workshop group ESHRE - ASRM; anovulation and infertility> 1 year. In fact, according to the Rotterdam criteria, PCOS was diagnosed if 2 of the following 3 factors were met: a) oligo or anovulation, b) clinical and / or biochemical signs of hyperandrogenism and c) polycystic ovaries.

[0162] Patients were excluded if other conditions caused ovulatory dysfunction, such as hyperprolactinemia or hypothyroidism or androgen excess, such as adrenal hyperplasia or Cushing's syndrome, and also in case of ingestion of other drugs that could potentially influence ovulation .

[0163] All patients received myo-inositol (Inofolic®, Lo.Li. Pharma, Rome, Italy), containing 2 g of myo-inositol and 0.2 mg of folic acid in the dose of two sachets a day before meals in order to induce ovulation.

[0164] Folic acid was included in the formulation considering that all women enrolled were of childbearing age when they tried to conceive without success. Folic acid supplementation is actually suggested if pregnancy occurs. However, as discussed above, folic acid is not itself necessary for the observed therapeutic effect. In fact, several controlled clinical studies related to the treatment of PCOS were carried out using folic acid as a placebo and determined that no specific effects attributable to folic acid were found in the selected population (see, for example, Costantino D, Minozzi G, Minozzi E, Guaraldi C. Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial. Eur Rev Med Pharmacol Sci 2009; 13: 105–10; Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM. inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol. 2008; 24: 139–44; and Gerli S,

Papaleo E, Ferrari A, Di Renzo GC. Randomized, double blind placebo- controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. Eur Rev Med Pharmacol Sci 2007; 11: 347–54). Consequently, the technical effect described here related to the treatment of infertility or subfertility, in particular infertility or subfertility caused by PCOS or anovulation, as well as related to the treatment of PCOS or anovulation itself, can be obtained with inositol and alpha-lactalbumin in double combination alone, without a source of folate, for example, folic acid.

[0165] Ovulation was assessed using ultrasound exam on days 12, 14 and 20 of the cycle. The treatment was carried out for three months.

[0166] The characteristics of the study participants are shown in Table

3.

Table 3: Baseline characteristics of admitted patients (n = 20) Age (years) 27 ± 4 Height (cm) 165.2 ± 5.6 Weight (kg) 72.0 ± 14.3 BMI (kg / m2) 26, 5 ± 5.5 Data presented as mean ± SD

[0167] After treatment with myo-inositol, 13 of the 20 women (65%) ovulated, while 7 (35%) were resistant and did not ovulate. Thus, in the present study, 7 of the 20 original women suffering from PCOS (35%) did not respond to treatment with myo-inositol alone. These 7 non-responders became the subject of a second phase of the study, in which they received treatment with myo-inositol in combination with alpha-lactalbumin.

[0168] Specifically, plasma levels of myo-inositol were tested in these patients who did not respond; an average value of 17 ± 3.5 µmol / l of myo-inositol was observed. Then, a treatment with 2 g of myo-inositol, 0.2 mg of folic acid and 50 mg of alpha-lactalbumin was carried out in doses of two powder sachets a day before meals for the next three months. Of the 7 patients resistant to myo-inositol after combined treatment with myo-inositol and alpha-lactalbumin, 5 of the original non-responders (ie, 71% of the original non-responders) ovulated. Plasma levels of myo-inositol at the end of treatment were significantly higher than the baseline (35 ± 3.8 µmol / l versus 17 ± 3.5 µmol / l, the latter having been measured at the beginning of the second phase of the study ) and were comparable to patients who responded positively to treatment with myo-inositol only (38 µmol / l). The data obtained in this study are shown below in Table 4.

Table 4: Results of the mean plasma concentration of myo-inositol and ovulation in 7 patients unresponsive to treatment with myo-inositol.

Plasma levels of myo-inositol Ovulation Treatments T0 T3 T3 average µmol / l (± SD) average µmol / l (± SD) (number of patients) 3-month treatment with myo- - 17 (3.5) 0 inositol treatment 3 months (additional) 17 (3.5) 35 (3.8) 5 with myo-inositol + alpha-lactalbumin

[0169] As the results above clearly indicate, the combination of alpha-lactalbumin with inositol, for example, myo-inositol, in the treatment of PCOS allows a significant improvement in the treatment of patients with PCOS who would otherwise be resistant to treatment with only myo-inositol. Specifically, a total of 71% of patients who were otherwise resistant to treatment with myo-inositol alone and who would continue to suffer from anovulation and resulting infertility after treatment with myo-inositol alone, ovulated by combining myo-inositol with alpha- lactalbumin. The combination of alpha-lactalbumin with myo-inositol therefore represents a significant improvement in the treatment of PCOS, thereby restoring ovulation and greatly increasing the chances of a desired pregnancy in many women who would otherwise remain infertile. The data from the above experiment strongly suggests that this improvement is due to the ability of alpha-lactalbumin to significantly increase the absorption of inositol, for example, myo-inositol, effectively increasing the amount of myo-inositol available in the blood to exert a beneficial effect.

Example 4 Clinical Evaluation in Women Affected by Idiopathic Infertility

[0170] The present study aims to develop an effective therapy in women suffering from idiopathic infertility based on the improved absorption of inositol, for example, myo-inositol, when administered in combination with alpha-lactalbumin. Specifically, while the treatment of idiopathic infertility with only myo-inositol correlates with an improvement in the disease in a significant number of women, there are still women who still do not respond to treatment with myo-inositol alone. The present inventors have therefore sought to determine whether the higher level of myo-inositol absorption observed when administering myo-inositol in conjunction with alpha-lactalbumin can enable the successful treatment of patients with idiopathic infertility who had not previously responded to the treatment with myo-inositol only. In this case, then the treatment of idiopathic infertility with inositol in combination with alpha-lactalbumin, for example, myo-inositol in combination with alpha-lactalbumin, would represent a significant therapeutic advance, allowing the treatment of idiopathic infertility in previously recalcitrant cases, thus substantially expanding the therapeutic benefit of inositol, for example, myo-inositol, in the treatment of idiopathic infertility.

[0171] The present study included 40 women affected by idiopathic infertility. Inclusion criteria were: women affected by idiopathic infertility, as defined below, aged between 30 and 40 years, who were not receiving any therapy with drugs that potentially influence ovulation. The patients received a complete evaluation and were tested for various diseases, as described below. The positive test for any of these diseases tested was sufficient to exclude a patient as being "idiopathically infertile". Specifically, patients were excluded from this trial if they were diagnosed as positive for any of the following: hyperprolactinemia, hypothyroidism, Cushing's syndrome, adrenal hyperplasia, obesity, polycystic ovary syndrome (PCOS) or anovulation. The person skilled in the art can routinely diagnose each of the conditions mentioned above. For example, hyperprolactinemia can be diagnosed when serum prolactin levels are greater than 20 g / L, as described in Serri et al, for example. CMAJ, 2003, 169 (6): 575-581. Hypothyroidism can be diagnosed when the TSH serum level is greater than 4.5 mIU / L (Garber et al., CLINICAL PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS:

COSPONSORED BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND THE AMERICAN THYROID ASSOCIATION; Endocrine Practice vol. 18 No. 6, 2012). Cushing's syndrome can be diagnosed according to Nieman et al., J. Clin. Endocrinol. Metab., 2008, 93 (5): pages 1526-1540. Adrenal hyperplasia can be diagnosed according to Witchel et al., Int.J.Pediatr.Endocrinol., 2010: 625105. Obesity can be diagnosed when the body mass index (BMI) is greater than

30.

[0172] The “treatment” of idiopathic infertility, as carried out in the present study, was considered to be the improvement or at least temporary abolition of a pathological state in which, despite repeated attempts over a long period of pregnancy, for example, about 12 months, no pregnancies have been achieved. The main reading was the completion of biochemical pregnancy as assessed using an assay (HCG Combo Card, Shanghai Chemtron Biotech Co., Ltd., catalog. No. 6011C31-4) for human chorionic beta gonadotropin (beta hCG). Biochemical pregnancy was achieved when the sample was positive for beta hCG, 14 days after ovulation.

[0173] The characteristics of the study participants are shown in Table

5. Table 5: Baseline characteristics of admitted patients (n = 40) Age (years) 36.1 ± 1.2 BMI (kg / m2) 24.7 ± 1.3 Data presented as mean ± SD

[0174] The treatment was carried out in 2 phases:

[0175] In the first phase, all patients received myo-inositol (Inofolic®, Lo.Li. Pharma, Rome, Italy) containing 2 g of myo-inositol and 0.2 mg of folic acid in powder form in one dose two sachets a day before meals. This means that patients received this dose orally twice a day on an empty stomach for a total of 3 months (Table 6). This treatment allowed the identification of individuals resistant to myo-inositol.

[0176] In the second phase, patients who did not become pregnant, classified as "patients resistant to myo-inositol", were treated later. They received 2 g of myo-inositol, 0.2 mg of folic acid and 50 mg of alpha-lactalbumin orally in doses of two powder sachets a day before meals for three months (Table 7).

[0177] The results of the present experiment are summarized in Tables 6 and 7, below.

Table 6: First treatment phase: myo-inositol (2 g) for 3 months Number of having a pregnancy No pregnancy%% patients biochemistry biochemistry 40 21 52.5 19 47.5

[0178] After treatment with myo-inositol, 21 of the 40 women (52.5%) achieved biochemical pregnancy, while 19 (47.5%) did not achieve biochemical pregnancy. Thus, in the present study, 19 of the 40 original women who suffer from idiopathic infertility (47.5%) did not respond to treatment with myo-inositol alone, that is, without alpha-lactalbumin. These 19 non-responders “resistant to myo-inositol” became the subjects of a second phase of the study, in which they received treatment with myo-inositol in combination with alpha-lactalbumin.

Table 7: Second treatment phase: myo-inositol (2 g) and alpha-lactalbumin (50 mg) for 3 months Number of Pregnancy No pregnancy%% biochemical resistance bi. ins. 19 12 63.2 7 36.8

[0179] After treatment with myo-inositol in combination with alpha-lactalbumin, 12 of the 19 women “resistant to myo-inositol” (63.2% of this group) achieved biochemical pregnancy, while 7 (36.8% of this group) did not achieve biochemical pregnancy.

[0180] Administration of a combination of myo-inositol with alpha-

lactalbumin overcame many cases of resistance to inositol, achieving successful therapy and increasing the chance of getting biochemically pregnant from 52.5% (21 out of 40 women in phase 1) to 82.5% overall (33 out of 40 women who get pregnant in phases) combined 1 and 2). As described above in Example 3, in the context of the treatment of PCOS, equivalent considerations regarding the presence of a source of folate in the composition also apply in the present context of the treatment of infertility that has its origin in idiopathic infertility and in the context of the treatment of idiopathic infertility itself. In particular, the technical effect described here related to the treatment of infertility having its origin in idiopathic infertility, as well as related to the treatment of idiopathic infertility itself, can be obtained with inositol and alpha-lactalbumin in double combination alone, without a source of folate , for example, folic acid.

[0181] As the results above clearly indicate, the combination of alpha-lactalbumin with inositol, for example, myo-inositol, in the treatment of idiopathic infertility allows a significant improvement in the treatment of patients with idiopathic infertility who would otherwise remain resistant treatment with myo-inositol only (women "resistant to myo-inositol"). Specifically, 63.2% of patients who were otherwise resistant to treatment with myo-inositol alone and who would continue to suffer from idiopathic infertility after treatment with myo-inositol alone, became biochemically pregnant by combining myo-inositol with alpha-lactalbumin. The combination of alpha-lactalbumin with myo-inositol thus represents a significant improvement in the treatment of idiopathic infertility, thereby greatly increasing the chances of a desired pregnancy in many women who would otherwise remain infertile.

Claims (26)

Claims 1. Composition, characterized by comprising inositol and alpha-lactalbumin, in which inositol and alpha-lactalbumin are present in a respective weight ratio from 1: 1 to 50: 1. 2. Composition according to claim 1, characterized in that inositol and alpha-lactalbumin are present in a respective weight ratio from 8: 1 to 50: 1, from 30: 1 to 50: 1, from 33: 1 to 43: 1 or 40: 1. Composition according to any one of claims 1 to 2, characterized in that inositol is chosen from myo-inositol, D-chiro-inositol or a mixture of these in any weight ratio. Composition according to any one of claims 1 to 3, characterized in that it comprises:  500 to 4000 mg of inositol;  1000 to 3000 inositol;  2000 mg of inositol;  10 to 500 mg of alpha-lactalbumin;  20 to 100 mg of alpha-lactalbumin;  30 to 70 mg of alpha-lactalbumin; or  50 mg of alpha-lactalbumin. Composition according to any one of claims 1 to 4, characterized in that it comprises 2000 mg of myo-inositol and 50 mg of alpha-lactalbumin. Composition according to any one of claims 1 to 5, characterized in that it additionally comprises a source of folate, preferably folic acid. 7. Combination of inositol and alpha-lactalbumin, characterized by being for use as a medicine. 8. Combination of inositol and alpha-lactalbumin for use, according to claim 7, characterized in that inositol and alpha-lactalbumin are used in a respective weight ratio from 1: 1 to 50: 1, from 8: 1 to 50 : 1, 30: 1 to 50: 1, 33: 1 to 43: 1 or 40: 1. 9. Combination of inositol and alpha-lactalbumin for use, according to claim 7 or 8, characterized in that  inositol is chosen from myo-inositol, D-chiro-inositol or a mixture of these in any weight ratio; or  the combination is in the form of a composition, as defined in any one of claims 1 to 6. 10. Use of inositol, characterized by being to prepare a medication to treat or prevent infertility or subfertility in an individual, in which the treatment or prevention comprises administering inositol to the individual in combination with alpha-lactalbumin. 11. Use of inositol, according to claim 10, characterized by infertility or subfertility being infertility or subfertility caused by polycystic ovary syndrome (PCOS) or anovulation or in which infertility originates from idiopathic infertility. 12. Use of inositol, characterized by being to prepare a drug to treat or prevent polycystic ovary syndrome (PCOS) or anovulation or idiopathic infertility in an individual, where the treatment or prevention involves administering the individual's inositol in combination with alpha -lactalbumin. Use of inositol according to any one of claims 10 to 12, characterized in that the treatment or prevention comprises administering inositol and alpha-lactalbumin to the individual not simultaneously within a given combined administration of a given regimen. 14. Use of inositol according to claim 13, characterized by the combined administration of inositol and alpha-lactalbumin comprising  administering inositol to the individual before administering alpha-lactalbumin to the individual; or  administer inositol to the individual after administering alpha- lactalbumin to the individual. 15. Use of inositol according to any one of claims 10 to 12, characterized in that the treatment or prevention comprises administering inositol to the individual simultaneously with alpha-lactalbumin. 16. Use of Inositol according to any one of claims 12 to 15, characterized in that the treatment or prevention comprises administering the combination of inositol and alpha-lactalbumin in a respective weight ratio from 1: 1 to 50: 1, from 8: 1 to 50: 1, 30: 1 to 50: 1, 33: 1 to 43: 1, or 40: 1. 17. Use of inositol, according to claim 16, characterized in that the treatment or prevention comprises administering to the individual:  500 to 4000 mg of inositol;  1000 to 3000 mg of inositol;  2000 mg of inositol;  10 to 500 mg of alpha-lactalbumin;  20 to 100 mg of alpha-lactalbumin;  30 to 70 mg of alpha-lactalbumin; or  50 mg of alpha-lactalbumin. 18. Use of inositol according to any one of claims 10 to 17, characterized in that inositol is chosen from myo-inositol, D-chiro-inositol or a mixture of these in any weight ratio. 19. Use of inositol, for use according to any one of claims 10 to 18, characterized in that the treatment or prevention further comprises administering to the individual a source of folate, preferably folic acid, in combination with inositol and alpha-lactalbumin. 20. Use of inositol according to claim 19, characterized in that the combination of inositol and alpha-lactalbumin is in the form of a composition comprising inositol and alpha-lactalbumin. 21. Use of inositol according to claim 20, characterized in that the composition is a composition, as defined in any one of claims 1 to 6. 22. Kit, characterized by comprising  inositol in a first container; and  alpha-lactalbumin in a second container. 23. Food or drink product, characterized by comprising inositol and alpha-lactalbumin in which the respective weight ratio between inositol and alpha-lactalbumin is from 1: 1 to 50: 1. 24. Food or drink product according to claim 23, characterized in that it comprises inositol and alpha-lactalbumin in a respective weight ratio from 8: 1 to 50: 1, from 30: 1 to 50: 1, from 33: 1 to 43: 1 or 40: 1. 25. Food or drink product according to claim 23 or 24, characterized in that it comprises:  500 to 4000 mg of inositol;  1000 to 3000 mg of inositol;  2000 mg of inositol  10 to 500 mg of alpha-lactalbumin;  20 to 100 mg of alpha-lactalbumin;  30 to 70 mg of alpha-lactalbumin; or  50 mg of alpha-lactalbumin. 26. Food or drink product according to any one of claims 23 to 25, characterized in that it comprises 2000 mg of myo-inositol and 50 mg of alpha-lactalbumin, or 600 mg of myo-inositol and 50 mg of alpha-lactalbumin.